"A QUINOLONE DERIVATIVE HAVING A 3-ALKYL-3-AMINOPYRROLIDINYL GROUP"

Abstract

A quinolone derivative having a 3-aminopyrrolidinyl group which is tetra- substituted at position 3 and 4 in that it is represented by following formula (I): or a salt of the kind such as herein described or a hydrate thereof, wherein R1 and R2 each represents hydrogen atom; R3 represents an alkyl group containing 1 to 6 carbon atoms, which being optionally substituted with halogen atom; R4 and R5 together represent (a) a 3- to 6-membered cyclic structure including the carbon atom shared by R4 and R5 to form a spirocyclic structure with the pyrrolidine ring; or (b) exomethylene group bonding to the pyrrolidine ring by double bond; R6 and R7, each represents hydrogen atom; R8 represents a halogen-substituted cycloalkyl group containing 3 to 6 carbon atoms; R9 represents hydrogen atom or an alkyl group containing 1 to 6 carbon atoms; X1 represents hydrogen atom or a halogen atom; and A represents a moiety represented by formula (II): wherein X2 represents an alkyl group containing 1 to 6 carbon atoms or an alkoxy group containing 1 to 6 carbon atoms.

Full Text

The present invention relates to a quinolone derivative having a 3-aminopyrrolidinyl group.
TECHNICAL FIELD [0001]
This invention relates to a quinolone synthetic antibacterial drug which is useful as a drug for human, animals, or fish, or as a antibacterial preservatives.
[BACKGROUND ART]
[0002]
Since discovery of norfloxacin, antibacterial activity and pharmacokinetics of quinolone synthetic antibacterial drugs (including those containing pyridobenzoxazine skeleton) have been greatly improved, and, today, they are used in chemotherapy for infections including almost all systemic infections, and a large number of drugs are in clinical use (see Patent document 1 or 2).
[0003]
However, bacteria exhibiting low sensitivity for quinolone synthetic antibacterial drugs have been recently increasing in its number in clinical field. For example, bacteria which are resistant to drugs other than quinolone synthetic antibacterial drugs, and which also exhibit low sensitivity to quinolone synthetic antibacterial drugs are increasing such as Gram positive coccus like Staphylococcus aureus (MRSA) and. pneumococcus (PRSP) insensitive to ß-lactam antibiotics and enterococcus (VRE) insensitive to aminoglycoside antibacterial drugs. Accordingly, there is a strong clinical demand for a drug exhibiting an improved effectiveness to Gram positive coccus.
[0004]
In the meanwhile, antibacterial activity of recently developed quinolone synthetic antibacterial compounds are by far stronger than former quinolone synthetic antibacterial compounds (see Patent documents 3 or 4) . However, many such quinolone compound having high antibacterial activity have been reported to produce side effects based on physiological or pharmacological action not observed in the former quinolone synthetic antibacterial compounds. For example, restrictions are imposed on
the administration of some compounds due to side effects such as development of abnormal blood glucose level, cardiotoxicity, or delayed allergy, or development of convulsion, and development and use as a drug have been abandoned in some compounds. In other words, many compounds have been found to be insufficient in their suitability as a drug due to the strong side effects despite their high antibacterial activity. Accordingly, a drug design methodology which is different from former compounds is required to thereby prevent the situation that a highly antibacterial compound can not be developed as a drug due to production of side effects. In other words, a design methodology is required that is capable of producing a compound which has a considerably high antibacterial activity comparable or similar to those of the conventional compounds, and at the same time, which is provided with suitability for a drug that allows use of the compound as a drug, for example, high safety without side effects.
[0005]
Exemplary side effects which have been reported for the quinolone synthetic antibacterial agents include induction of convulsion associated with concomitant use of a nonsteroidal anti-inflammatory agent, central action (relatively light central nerve disorders such as reeling, headache, and insomnia as well as serious side effects such as development of lethal convulsion), phototoxicity (photosensitivity), hepatotoxicity, and cardiotoxicity (an abnormality observed as an abnormality of electrocardiogram which induces lethal arrhythmia), delayed allergy, and abnormal glucose blood level (see Non-patent documents 1 to 3).
[0006]
Of the side effects as mentioned above, significant recently reported clinical cases involve cardiotoxicity (a heart abnormality inducing lethal arrhythmia which is observed as an abnormality of electrocardiogram with prolonged QT or QTc interval). Some commercially available quinolone antibacterial agents have been reported to produce clearly prolonged QT or QTc interval including some serious cases (abnormality of electrocardiogram inducing lethal arrhythmia) (Non-patent documents 1 to 3). Also reported are side effects such as induction of rash, which is a esult of delayed allergy, and abnormal blood glucose level.
[0007]
Accordingly, in order to enable use the quinolone antibacterial agent as a human or animal drug, there is a demand for a quinolone synthetic antibacterial agent which is provided with an improved safety with weaker side effects such as induction of convulsion associated with concomitant use of a nonsteroidal anti-inflammatory agent, central action, phototoxicity (photosensitivity), and hepatotoxicity, as well as side effects such as cardiotoxicity, delayed allergy, and abnormal glucose blood level. In other words, there is a strong demand for a quinolone compound simultaneously provided with a strong antibacterial activity and selective toxicity.
[Patent Document 1] Japanese Patent Application Laid-Open No. (JP-A) 61-282382
[Patent Document 2] JP-A 63-45261
[Patent Document 3] JP-A 2-231475
[Patent Document 4] JP-A 3-95176
[Non-patent Document 1] Hiroyuki Kobayashi Ed., "Clinical Applications of New-quinolone Agents", lyaku-Journal-Sha (2001)
[Non-patent Document 2] Drugs, Vol. 62, No. 1, page 13 (2002)
[Non-patent Document 3] Toxicology Letters, Vol. 127, page 269 (2002)
DISCLOSURE OF THE INVENTION PROBLEMS TO BE SOLVED BY THE INVENTION [0008]
In view of the situation as described above, an object of the present invention is to provide a quinolone synthetic antibacterial agent and a therapeutic agent for an infection which exhibit broad spectrum and strong antibacterial activity for both Gram positive and Gram negative bacteria, and which are also highly safe.
MEANS FOR SOLVING THE PROBLEMS [0009] - [0011]
The inventors of the present invention have conducted investigation by focusing on a compound which has 3-aminopyrrolidinyl group at position 7 or equivalent position of a quinolone compound. In the course of the investigation, the
inventors found that a quinolone compound having an 3-aminopyrrolidinyl group which is tri- or tetra- substituted at positions 3 and 4 represented by the following formula:
(Formula I Removed)
which has substituent which is typically an aliphatic substituent on the carbon atom at position 3, and one or two substituents which are also typically an aliphatic substituent on the carbon atom at position 4 has a broad spectrum of strong antibacterial activity for Gram-positive and Gram-negative bacteria including drug resistant Gram positive cocci such as multiple drug resistant pneumococcus having the resistance for quinolone. The inventors also found that such quinolone compound has not only such high antibacterial activity but also lower cardiotoxicity compared to the quinolone antibacterial drugs whose cardiotoxicity has recently been reported in clinical practice as a side effect of the quinolone antibacterial drugs. It was also found that this compound has reduced risk of producing side effects such as delayed allergy and abnormal blood glucose level. It was also found that this compound has excellent oral absorptivity, organ permiability, and excretion rate in urine. Accordingly, the inventors of the present invention have found that the quinolone compound represented by formula (I) is a quinolone synthetic antibacterial drug which has excellent drug properties including excellent antibacterial activity and high safety, and also excellent pharmacokinetics. The present invention has been completed on the bases of such findings.
[0012]
Accordingly, the present invention provides a compound represented by following formula (I):
[0013]
(Formula I Removed)
or a salt or a hydrate thereof, [0014]
wherein R1 represents hydrogen atom, an alkyl group containing 1 to 6 carbon atoms, a cycloalkyl group containing 3 to 6 carbon atoms, or a substituted carbonyl group derived from an amino acid, a dipeptide, or a tripeptide; the alkyl group being optionally substituted with a substituent selected from the group consisting of hydroxy group, amino group, halogen atom, an alkylthio group containing 1 to 6 carbon atoms, and an alkoxy group containing 1 to 6 carbon atoms;
R2 represents hydrogen atom, an alkyl group containing 1 to 6 carbon atoms, or a cycloalkyl group containing 3 to 6 carbon atoms; the alkyl group being optionally substituted with a substituent selected from the group consisting of hydroxy group, amino group, halogen atom, an alkylthio group containing 1 to 6 carbon atoms, and an alkoxy group containing 1 to 6 carbon atoms;
R3 represents an alkyl group containing 1 to 6 carbon atoms, a cycloalkyl group containing 3 to 6 carbon atoms, an alkenyl group containing 2 to 6 carbon atoms, or an alkynyl group containing 2 to 6 carbon atoms; the alkyl group being optionally substituted with a substituent selected from the group consisting of hydroxy group, amino group, halogen atom, an alkylthio group containing 1 to 6 carbon atoms, and an alkoxy group containing 1 to 6 carbon atoms;
R4 and R5 independently represent hydrogen atom, halogen atom, an alkyl group containing 1 to 6 carbon atoms, an alkoxy group containing 1 to 6 carbon atoms, an alkenyl group containing 2 to 6 carbon atoms, an alkynyl group containing 2 to 6 carbon atoms, or an optionally substituted cycloalkyl group containing 3 to 6 carbon atoms; the alkyl group, the alkoxy group, the alkenyl group,
and the alkynyl group being either a straight chain or branched group; the alkyl group being optionally substituted with a substituent selected from the group consisting of hydroxy group, amino group, halogen atom, an alkylthio group containing 1 to 6 carbon atoms, and an alkoxy group containing 1 to 6 carbon atoms; and with the proviso that R4 and R5 are not simultaneously hydrogen atom,- or
the substituents R4 and R5 combine together to form (a) a 3-to 6-membered cyclic structure including the carbon atom shared by R4 and R5 to form a spirocyclic structure with the pyrrolidine ring, the thus formed spiro ring optionally containing oxygen atom or sulfur atom as a ring member atom, and optionally being substituted with a halogen atom or an alkyl group containing 1 to 6 carbon atoms optionally having a substituent; or (b) exomethylene group bonding to the pyrrolidine ring by double bond, the exomethylene group optionally having 1 or 2 substituents selected from hydroxy group, amino group, halogen atom, an alkylthio group containing 1 to 6 carbon atoms, and an alkoxy group containing 1 to 6 carbon atoms;
R6 and R7 independently represent hydrogen atom or an alkyl group containing 1 to 6 carbon atoms;
R8 represents a halogen-substituted alkyl group containing 1 to 6 carbon atoms, a halogen-substituted cycloalkyl group containing 3 to 6 carbon atoms, a halogen-substituted phenyl group, or a halogen-substituted heteroaryl group;
R9 represents hydrogen atom, phenyl group, acetoxymethyl group, pivaloyl oxymethyl group, ethoxycarbonyl group, choline group, dimethyl aminoethyl group, 5-indanyl group, phthalidinyl group, 5-alkyl-2-oxo-1,3-dioxol-4-ylmethyl group, 3-acetoxy-2-oxobutyl group, an alkyl group containing 1 to 6 carbon atoms, an alkoxymethyl group containing 2 to 7 carbon atoms, or a phenylalkyl group comprising an alkylene group containing 1 to 6 carbon atoms and phenyl group;
X1 represents hydrogen atom or a halogen atom; and
A represents nitrogen atom or a moiety represented by formula (II): [0015]
(Formula II Removed)
[0016]
wherein X2 represents hydrogen atom, an alkyl group containing 1 to 6 carbon atoms, an alkoxy group containing 1 to 6 carbon atoms, cyano group, halogen atom, a halogen-substituted methyl group, or a halogenomethoxy group; or X2 and R8 may combine together to form a cyclic structure including a part of the mother nucleus, the thus formed ring optionally containing oxygen atom, nitrogen atom, or sulfur atom as a ring constituting atom, and optionally being substituted with an alkyl group containing 1 to 6 carbon atoms optionally having a substituent.
[0017]
The present invention also provides a drug containing the compound represented by the formula (I) or a salt or a hydrate thereof as its effective ingredient.
[0018]
The present invention also provides a method for treating a disease by administering the compound represented by the formula (I) or a salt or a hydrate thereof. The present invention also provides use of the compound represented by the formula (I) or a salt or a hydrate thereof for producing a drug.
EFFECT OF THE INVENTION [0019]
The present invention provides a quinolone synthetic drug which has excellent drug properties such as strong antibacterial activity not only for Gram negative bacteria but also for Gram-positive cocci which have become less sensitive to quinolone antibacterials, high safety, and favorable pharmacokinetics.
[BRIEF DESCRIPTION OF THE DRAWING] [0020]
[FIG. 1] a graph showing MBI action of Comparative compound 1 and the compound of Example 9 against CYP3A4.
[FIG. 2] a graph showing therapeutic effects of Comparative compound 1 and the compound of Example 9 in mouse local lung infection model by PRSP.
[FIG. 3] a view showing the results of X ray structural analysis for the compound produced in Reference Example 107.
[FIG. 4] a graph showing therapeutic effects of Comparative compound 1 and the compound of Example 9 in rat simple cystitis model by E. coli.
[BEST MODES FOR CARRYING OUT THE INVENTION] [0021]
First, the substituents of the formula (I) are described. [0022]
R1 represents hydrogen atom, an alkyl group containing 1 to 6 carbon atoms, a cycloalkyl group containing 3 to 6 carbon atoms, or a substituted carbonyl group derived from an amino acid, a dipeptide, or a tripeptide. When R1 is an alkyl group, it may be substituted with a substituent selected from the group consisting of hydroxy group, amino group, halogen atom, an alkylthio group containing 1 to 6 carbon atoms, and an alkoxy group containing 1 to 6 carbon atoms.
R2 represents hydrogen atom, an alkyl group containing 1 to 6 carbon atoms, or a cycloalkyl group containing 3 to 6 carbon atoms, When R2 is an alkyl group, it may be substituted with a substituent selected from the group consisting of hydroxy group, amino group, halogen atom, an alkylthio group containing 1 to 6 carbon atoms, and an alkoxy group containing 1 to 6 carbon atoms. [0023]
When R1 or R2 is an alkyl group, the alkyl group may be either a straight chain or a branched alkyl group. The alkyl group is preferably methyl group, ethyl group, propyl group, or isopropyl group, and more preferably, methyl group or ethyl group, and most preferably methyl group.
When R1 or R2 is an alkyl group having hydroxy group or amino group as its substituent, the alkyl group may be any straight chain or branched alkyl containing 1 to 6 carbon atoms, and the alkyl group is preferably substituted with the substituent at its terminal carbon atom. The alkyl group having hydroxy group is preferably an alkyl group containing up to 3 carbon atoms, and preferable examples include hydroxymethyl group, 2-hydroxyethyl group, 2-hydroxypropyl group, and 3-hydroxypropyl group. The alkyl group having amino group is preferably an alkyl group containing up to 3 carbon atoms, and preferable examples include aminomethyl
group, 2-aminoethyl group, 2-aminopropyl group, and 3-aminopropyl group. [0024]
When R1 or R2 is an alkyl group having a halogen atom as its substituent, the alkyl group may be any of the straight chain or branched alkyl groups containing 1 to 6 carbon atoms, and the halogen atom is preferably fluorine atom. The number of the fluorine substitution is not limited and the substitution may be mono- to perfluoro substitution. Exemplarily preferable substituens as halogenated alkyl gruoup are halogen-substituted alkyl groups include monofluoromethyl group, difluoromethyl group, trifluoromethyl group, and 2,2,2-trifluoroethyl group. [0025]
When R1 or R2 is an alkyl group having an alkylthio group or an alkoxy group as its substituent, the alkyl group may be either a straight chain or a branched alkyl group, and the alkyl moiety of the alkylthio group and the alkoxy group may also be either a straight chain or a branched alkyl moiety. Exemplary alkyl groups having an alkylthio group include an alkylthiomethyl group, an alkylthioethyl group, and an alkylthiopropyl group, and the alkylthio group in such groups is preferably the one containing 1 to 3 carbon atoms. More preferable are methylthiomethyl group, ethylthiomethyl group, and methylthioethyl group. Exemplary alkyl groups having an alkoxy group include an alkoxymethyl group, an alkoxyethyl group, and an alkoxypropyl group, and the alkoxy group in such groups is preferably the one containing 1 to 3 carbon atoms. More preferable are methoxymethyl group, ethoxymethyl group, and methoxyethyl group. [0026]
When R1 or R2 is a cycloalkyl group, it is preferably cyclopropyl group or cyclobutyl group, and more preferably, cyclopropyl group. Substituent of the cycloalkyl group may be one or more group selected from an alkyl group containing 1 to 6 carbon atoms, halogen atom, amino group, and hydroxy group, and examples of the preferable substituent include methyl group, ethyl group, fluorine atom, chlorine atom, amino group, and hydroxy group. [0027]
Preferable combination of R1 and R2 include the combination wherein R1 is hydrogen atom, an alkyl group, a cycloalkyl group, or
a substituted carbonyl group derived from an amino acid, a dipeptide, or a tripeptide and R2 is hydrogen atom. Among these, the preferable combination is the one wherein R1 is hydrogen atom, an alkyl group, or a cycloalkyl group, and R2 is hydrogen atom. The alkyl group in such case is preferably methyl group or ethyl group, and more preferably, methyl group. The cycloalkyl group is preferably cyclopropyl group or cyclobutyl group, and more preferably cyclopropyl group. The combination of R1 and R2 is more preferably the combination wherein both R1 and R2 are hydrogen atom, or the combination wherein one of R1 and R2 is hydrogen atom, and the other is methyl group, ethyl group, fluoroethyl group, or cyclopropyl group. [0028]
A quinolone derivative wherein R1 is a substituted carbonyl group derived from an amino acid, a dipeptide, or a tripeptide, and R2 is hydrogen atom is useful as a prodrug. The amino acid, dipeptide, or tripeptide used in producing such a prodrug is the one which is capable of producing a free amine compound by cleavage in the living body of the peptide bond between the carboxyl group and the amino group having R1 and R2 bonded thereto. Examples of the substituted carbonyl group used in producing such a prodrug include substituted carbonyl substituents derived from an amino acid such as glycine, alanine, or aspartic acid; a dipeptide constituted from glycine, alanine, or asparagine such as glycine-glycine, glycine-alanine, or alanine-alanine; and a tripeptide constituted from glycine, alanine, or asparagine such as glycine-glycine-alanine, or glycine-alanine-alanine.
[0029]
R3 represents an alkyl group containing 1 to 6 carbon atoms, a cycloalkyl group containing 3 to 6 carbon atoms, an alkenyl group containing 2 to 6 carbon atoms, or an alkynyl group containing 2 to 6 carbon atoms. When R3 is an alkyl group, it may be optionally substituted with a substituent selected from the group consisting of hydroxy group, amino group, halogen atom, an alkylthio group containing 1 to 6 carbon atoms, and an alkoxy group containing 1 to 6 carbon atoms.
[0030]
When R3 is an alkyl group, the alkyl group may be either a straight chain or a branched alkyl group. The alkyl group is preferably methyl group, ethyl group, propyl group, or isopropyl
group. Among these, the preferred is methyl group or ethyl group, and the more preferred is methyl group.
The cycloalkyl group containing 3 to 6 carbon atoms is preferably cyclopropyl group or cyclobutyl group, and more preferably cyclopropyl group.
The alkenyl group containing 2 to 6 carbon atoms is preferably the one having one double bond, which is not particularly limited for its Ication. The preferred are vinyl group, propenyl group, and butenyl group. The alkynyl group containing 2 to 6 carbon atoms is also preferably the one containing one triple bond, which is not particularly limited for its location. The preferred are ethynyl group, propynyl, and buthynyl. Among those mentioned above, the preferred are vinyl group and ethynyl group. [0031]
When R3 is an alkyl group, it may be optionally substituted with a substituent selected from the group consisting of hydroxy group, amino group, halogen atom, an alkylthio group containing 1 to 6 carbon atoms, and an alkoxy group containing 1 to 6 carbon atoms.
When the substituent of the alkyl group is hydroxy group or amino group, the alkyl group is preferably substituted with such substituent at the terminal carbon atom. Preferable examples of the alkyl group having hydroxy group are hydroxymethyl group, 2-hydroxyethyl group, 2-hydroxypropyl group, and 3-hydroxypropyl group, and preferable examples of the alkyl group having amino group are aminomethyl group, 2-aminoethyl group, 2-aminopropyl group, and 3-aminopropyl group. The alkyl group having the hydroxy group or the amino group is preferably methyl group or ethyl group having such group, and more preferably methyl group having such group, for example, hydroxymethyl group or aminomethyl group.
When the alkyl group has a halogen atom as its substituent, the alkyl group may be any of the straight chain or branched alkyl groups containing 1 to 6 carbon atoms. The preferred is methyl group or ethyl group having a halogen atom, and the more preferred is methyl group having a halogen atom. Preferable halogen atom is fluorine atom. The number of the fluorine substitution is not limited and the substitution may be mono- to perfluoro substitution. Exemplary halogen-substituted alkyl groups include monofluoromethyl group, difluoromethyl group, trifluoromethyl
group, and 2,2,2-trifluoroethyl group, and the preferred is monofluoromethyl group, difluoromethyl group, and trifluoromethyl group.
When the substituent of the alkyl group is an alkylthio group or an alkoxy group, the alkyl group may be either a straight chain or a branched alkyl group, and the alkyl moiety in the alkylthio group or the alkoxy group may also be either a straight chain or a branched alkyl group. The alkyl group having an alkylthio group is preferably an alkylthiomethyl group or an alkylthioethyl group, and the alkylthio group is preferably the one containing I or 2 carbon atoms. The preferred are methylthiomethyl group, ethylthiomethyl group, and methylthioethyl group. The alkyl group having an alkoxy group is preferably an alkoxymethyl group or an alkoxyethyl group, and the alkoxy group is preferably the one containing 1 or 2 carbon atoms. The preferred are methoxymethyl group, ethoxymethyl group, and methoxyethyl group. The more preferred are methylthiomethyl group and methoxymethyl group.
[0032]
When R3 is a cycloalkyl group, the substituent is one or more group selected from the group consisting of an alkyl group containing 1 to 6 carbon atoms, halogen atom, amino group, and hydroxy group. Preferable examples of such substituent are methyl group, ethyl group, fluorine atom, and chlorine atom.
[0033]
Preferable examples of R3 include those containing 1 or 2 carbon atoms such as methyl group; ethyl group; vinyl group,-fluoro-substituted methyl group or ethyl group; methyl group or ethyl group having amino group or hydroxy group; and methyl group having thiomethyl group or methoxy group. R3 is most preferably methyl group or ethyl group.
[0034]
R4 and R5 independently represent hydrogen atom, halogen atom, an alkyl group containing 1 to 6 carbon atoms, an alkoxy group containing 1 to 6 carbon atoms, an alkenyl group containing 2 to 6 carbon atoms, an alkynyl group containing 2 to 6 carbon atoms, or an optionally substituted cycloalkyl group containing 3 to 6 carbon atoms. When R4 or R5 is an alkyl group, it may be substituted with a substituent selected from the group consisting of hydroxy group, amino group, halogen atom, an alkylthio group
containing 1 to 6 carbon atoms, and an alkoxy group containing 1 to 6 carbon atoms. R4 and R5 are not simultaneously hydrogen atom. R4 and R5 may also combine together to form
(a) a 3- to 6-membered cyclic structure including the carbon
atom shared by R4 and R5 to form a spirocyclic structure with the
pyrrolidine ring, the thus formed spiro ring optionally containing
oxygen atom or sulfur atom as a ring member atom, and optionally
being substituted with a halogen atom or an alkyl group containing
1 to 6 carbon atoms optionally having a substituent; or
(b) exomethylene group bonding to the pyrrolidine ring by
double bond, the exomethylene group optionally having 1 or 2
substituents selected from hydroxy group, amino group, halogen
atom, an alkylthio group containing 1 to 6 carbon atoms, and an
alkoxy group containing 1 to 6 carbon atoms.
[0035]
When R4 or R5 is an alkyl group, it may be either a straight chain or a branched alkyl group, and it may be methyl group, ethyl group, propyl group, or isopropyl group; more preferably methyl group or ethyl group; and most preferably methyl group.
When R4 or R5 is an alkyl group and this alkyl has hydroxy group or amino group as its substituent, the alkyl group is preferably substituted with such substituent at its terminal carbon atom. The alkyl group having hydroxy group is preferably the one containing up to 3 carbon atoms, and preferable examples include hydroxymethyl group, 2-hydroxyethyl group, 2-hydroxypropyl group, and 3-hydroxypropyl group. The alkyl group having amino group is preferably the one containing up to 3 carbon atoms, and preferable examples include aminomethyl group, 2-aminoethyl group, 2-aminopropyl group, and 3-aminopropyl group.
When R4 or R5 is an alkyl group and this alkyl group has a halogen atom as its substituent, the alkyl group may be either a straight chain or a branched alkyl group containing 1 to 6 carbon atoms, and the halogen atom is preferably fluorine atom. The number of the fluorine substitution is not limited and the substitution may be mono- to perfluoro substitution. Exemplarily preferable substituens as halogenated alkyl gruoup are halogen-substituted alkyl groups include monofluoromethyl group, difluoromethyl group, trifluoromethyl group, and 2,2,2-trifluoroethyl group.
[0036] When R4 or R5 is an alkyl group having an alkylthio group or an alkoxy group as its substituent, the alkyl group may be either a straight chain or a branched alkyl group, and the alkyl moiety in the alkylthio group or the alkoxy group may also be a straight chain or a branched alkyl group. The alkyl group having an alkylthio group is preferably an alkylthiomethyl group, an alkylthioethyl group, or an alkylthiopropyl group, and the alkylthio group is preferably the one containing 1 to 3 carbon atoms. More preferably, the alkyl group having an alkylthio group is methylthiomethyl group, ethylthiomethyl group, or methylthioethyl group. The alkyl group having an alkoxy group is preferably an alkoxymethyl group, an alkoxyethyl group, or an alkoxypropyl group, and the alkoxy group is preferably the one containing 1 to 3 carbon atoms. More preferably, the alkyl group having an alkoxy group is methoxymethyl group, ethoxymethyl group, or methoxyethyl group.
When R4 or R5 is a cycloalkyl group, it is preferably cyclopropyl group or cyclobutyl group, and more preferably cyclopropyl group. When R4 or R5 is a substituted cycloalkyl group, the substituent may be the same as the same case of R3 , and is at least one substituent selected from the group consisting of an alkyl group containing 1 to 6 carbon atoms, halogen atom, amino group, and hydroxy group. Preferable examples of such substituent are methyl group, ethyl group, fluorine atom, and chlorine atom. [0037]
When R4 or R5 is a halogen atom, it may be fluorine atom, chlorine atom, or iodine atom, and preferably, fluorine atom. [0038]
When R4 or R5 is an alkoxy group, it may be any of the alkoxy groups derived from the alkyl group as described above, and it is preferably an alkoxy group containing 1 to 3 carbon atoms. Exemplary such alkoxy groups include methoxy group and ethoxy group. [0039]
When R4 or R5 is an alkenyl group or an alkynyl group, these groups may be as defined above for R3. [0040]
When R4 and R5 combine together to form a spirocyclic structure, R4 and R5 together form a polymethylene chain containing 2 to 5 carbon atoms and opposite ends of the thus formed

polyraethylene chain bind to the carbon atom having the R4 and R5 attached thereto to thereby for a cyclic structure. The thus formed ring may have a size of 3-membered ring to six-membered ring, and among these, the preferred are 3-membered ring or 4-membered ring, and the more preferred are 3-membered ring. The methylene group in the polymethylene chain may be replaced with oxygen atom or sulfur atom to form a saturated heterocycle. The ring formed by R4 and R5 is optionally substituted with a halogen atom or an optionally substituted alkyl group containing 1 to 6 carbon atoms. Exemplary halogen atoms include fluorine atom and chlorine atom. The alkyl group may be either a straight chain or a branched alkyl group, and the preferred are methyl group, ethyl group, propyl group, and isopropyl group, and the more preferred are methyl group or ethyl group. This alkyl group is optionally substituted with a substituent which is preferably a halogen atom.
[0041]
When R4 and R5 together form an exomethylene group which binds to the pyrrolidine ring by double bond, a carbon-carbon double bond is formed by using the carbon atom at position 4 of the pyrrolidinyl group having the R4 and R5 attached thereto as one of the carbon atom. In such a case, the pyrrolidinyl substituent moiety has a structure represented by the following formula:
[0042]
(Formula Removed)
[0043]
wherein R41 and R51, both represents hydrogen atoms, or one of them represents a hydrogen atom and the other represents a substituent selected from the group consisting of hydroxy group, amino group, halogen atom, an alkylthio group containing 1 to 6 carbon atoms, or an alkoxy group containing 1 to 6 carbon atoms.
When the substituent of the exomethylene group is alkylthio group or alkoxy group, the alkyl moiety therof may be optionally substituted with a substituent selected from the group consisting
of hydroxy group, amino group, halogen atom, an alkylthio group containing 1 to 6 carbon atoms, and an alkoxy group containing 1 to 6 carbon atoms. Among these, the an alkylthio group containing 1 to 6 carbon atoms or the an alkoxyl group containing 1 to 6 carbon atoms is preferably an alkylthio or alkoxy group containing 1 to 3 carbon atoms, more preferably, methylthio group, ethylthio group, methoxy group, or ethoxy group, and still more preferably methylthio group or methoxy group.
Preferably, the exomethylene group is not substituted with a substituent other than hydrogen atom. However when the exomethylene group has a substituent, the substituent is preferably hydroxy group, amino group, fluorine atom, chlorine atom, methylthio group, or methoxy group. [0044]
Preferable combination of R4 and R5 is the one wherein one of R4 and R5 is hydrogen atom and the other is fluorine atom, methyl group, ethyl group, normal-propyl group, isopropyl group, normal-butyl group, cyclopropyl group, fluoromethyl group, methoxy group, vinyl group, or ethynyl group. Also preferred are R4 and R5 together forming cyclopropane ring or cyclobutane ring including the carbon atom shared by R4 and R5 to form a spirocyclic structure. Further, R4 and R5 preferably combine together forming an exoalkylene group containing 2 to 5 carbon atoms.
R4 or R5 is preferably a fluoroalkyl group, a fluoline atom, or spirocyclic structure or exomethylene group by the constructed by the combination of these
[0045]
R6 and R7 independently represent hydrogen atom or an alkyl group containing 1 to 6 carbon atoms. The alkyl group may be either a straight chain or a branched alkyl group, and the preferred are methyl group, ethyl group, propyl group, and isopropyl group. The more preferred are methyl group or ethyl group, and the most preferred is methyl group. Preferably, both R6 and R7 are hydrogen atom. [0046]
R8 represents a halogen-substituted alkyl group containing 1 to 6 carbon atoms, a halogen-substituted cycloalkyl group containing 3 to 6 carbon atoms, a halogen-substituted phenyl group, or a halogen-substituted heteroaryl group. [0047]
When R8 is a halogen-substituted alkyl group containing 1 to 6 carbon atoms, the alkyl group moiety may be either a straight chain or a branched group as exemplified by methyl group, ethyl group, propyl group, isopropyl group, butyl group, isobutyl group, sec-butyl group, and tert-butyl group. Among these, the preferred is ethyl group. The halogen atom substituting the alkyl group is preferably fluorine atom or chlorine atom, and more preferably fluorine atom. Examples of the halogen-substituted alkyl group include fluoromethyl group, 1-fluoroethyl group, and 2-fluoroethyl group, and the preferred is 2-fluoroethyl group.
When R8 is a halogen-substituted cycloalkyl group containing 3 to 6 carbon atoms, exemplary cyclic alkyl group include cyclopropyl group, cyclobutyl group, and cyclopentyl group, and the preferred is cyclopropyl group. Exemplary substituent halogen atoms include fluorine atom and chlorine atom, and the preferred is fluorine atom. Mono-substitution with the halogen atom is sufficient, and the preferred is monofluorocyclopropyl group, and the more preferred is cis-monofluorocyclopropyl group.
The halogen atom in the halogen-substituted phenyl group is preferably fluorine atom or chlorine atom, and more preferably, fluorine atom. The substitution with the halogen atom is preferably a mono- or di-substitution. The halogen-substituted phenyl groups is preferably 2-fluorophenyl group, 4-fluorophenyl group, or 2,4-difluorophenyl group.
The heteroaryl group in the halogen-substituted heteroaryl group may be a five-membered or a six-membered aromatic heterocyclic group containing one or more heteroatoms selected from nitrogen atom, sulfur atom, and oxygen atom. Among such heteroaryl groups, the preferred is a five-membered or a six-membered nitrogen-containing aromatic heterocyclic group containing 1 or 2 nitrogen atoms. Exemplary such groups include pyridyl group, pyrimidyl group, piperidinyl group, pyrrolidinyl group, morpholinyl group, pyrrolyl group, imidazolyl group, pyrazolyl group, pyridyl group, pyrimidinyl group, pyridazinyl group, pyrrolidinyl group, pyrrolynyl group, imidazolidinyl group, imidazolinyl group, pyrazolidinyl group, pyrazolinyl group, piperidyl group, and piperazinyl group, and among these, the preferred is pyridyl group. The halogen atom is preferably fluorine atom or chlorine atom, and more preferably fluorine atom.
The substitution with the halogen atom is preferably a mono- or di- substitution.
[0048]
R8 is preferably a halogen- substituted cycloalkyl group containing 3 to 6 carbon atoms, and preferably, a 2-halogenocyc lopropyl group, and more preferably a l,2-cis-2-halogenopropyl group, and particularly, a (lR,2S)-2-halogenocyc lopropyl group. The more preferable is monofluorocyclopropyl group, and in particular, cis-monof luorocyc lopropyl group. The most preferable is l,2-cis-2-f luorocyclopropyl group, and in particular, (lR,2S)-2-fluorocyclopropyl group.
[0049]
R9 represents hydrogen atom, phenyl group, acetoxymethyl group, pivaloyl oxymethyl group, ethoxycarbonyl group, choline group, dimethyl aminoethyl group, 5-indanyl group, phthalidinyl group, 5-alkyl-2-oxo-l, 3-dioxol-4-ylmethyl group, 3-acetoxy-2-oxobutyl group, an alkyl group containing 1 to 6 carbon atoms, an alkoxymethyl group containing 2 to 7 carbon atoms, or a phenylalkyl group comprising an alkylene group containing 1 to 6 carbon atoms and phenyl group .
R9 is preferably hydrogen atom.
[0050]
X1 represents hydrogen atom or a halogen atom. Preferable halogen atom is fluorine atom or chlorine atom, and the more preferred is fluorine atom. X1 is preferably fluorine atom or hydrogen atom.
[0051]
A represents nitrogen atom or a moiety represented by formula (II) :
[0052]
(Formula II Removed)
[0053]
wherein X2 represents an alkyl group containing 1 to 6 carbon atoms, an alkoxy group containing 1 to 6 carbon atoms, hydrogen atom, cyano group, halogen atom, a halogen- substituted methyl group, or a halogenomethoxy group. X2 together with R8 may combine together
to form a cyclic structure including a part of the mother nucleus, and the thus formed ring may optionally contain oxygen atom, nitrogen atom, or sulfur atom as a ring member atom, and the ring may be substituted with an alkyl group containing 1 to 6 carbon atoms optionally having a substituent.
[0054]
When A is a moiety represented by formula (II), and X2 is an alkyl group containing 1 to 6 carbon atoms, X2 may be either a straight chain or a branched alkyl group. Preferably, X2 is methyl group, ethyl group, propyl group, or isopropyl group, and among these, the preferred are methyl group and ethyl group, and the more preferred is methyl group. When X2 is an alkoxy group containing 1 to 6 carbon atoms, it may be any of the alkoxy group derived from the alkyl group as described above. Among those described above, X2 is preferably an alkyl group containing 1 to 3 carbon atoms or an alkoxy group containing 1 to 3 carbon atoms, and more preferably methyl group or methoxy group.
When X2 is a halogen atom, it is preferably fluorine atom or chlorine atom, and more preferably fluorine atom. When X2 is a halogen-substituted methyl group, the halogen atom is preferably fluorine atom or chlorine atom, and more preferably fluorine atom. Exemplary halogen-substituted methyl groups include fluoromethyl group, difluoromethyl group, and trifluoromethyl group. Similarly, when X2 is a halogenomethoxy group, the halogen atom is preferably fluorine atom or chlorine atom, and more preferably, fluorine atom. Exemplary halogenomethoxy groups include fluoromethoxy group, difluoromethoxy group, and trifluoromethoxy group.
[0055]
When A is a moiety represented by formula (II), X2 and R8 may combine together to form a cyclic structure containing a part of the quinolone skeleton (3 atoms, namely, the carbon atom having X2 bonded thereto; the nitrogen atom having R8 bonded thereto; and the carbon atom between the nuclei having X2 and R8 bonded thereto). The ring formed may preferably have a size of 5 to 7-membered ring, and the ring may be either saturated or unsaturated. This cyclic structure may also contain oxygen atom, nitrogen atom, or sulfur atom as a constituent atom of the ring, and this cyclic structure may be further substituted with an alkyl group containing 1 to 6 carbon atoms as described above for X2. The cyclic structure preferably contains oxygen atom, and it is preferably substituted
with a methyl group. Such partial structure is preferably a structure represented by the formula: -0-CH2-CH(-CH3) - (the carbon atom at the right end binds to nitrogen atom). [0056]
When A is a moiety represented by formula (II), and the substituent X2 does not form a cyclic structure, X2 is preferably methyl group, ethyl group, methoxy group, difluoromethoxy group, cyano group, or chlorine atom, and most preferably methyl group, methoxy group, or difluoromethoxy group.
When A is a moiety represented by formula (II), and the substituent X2 forms a cyclic structure, the preferred is the formation of 2,3-dihydro-3-methyl-7-oxo-7H-pyrido[1,2,3-de] [1,4] benzoxazine-6-carboxylic acid skeleton, and in particular, 3-(S)-methylpyridobenzoxazine skeleton. [0057]
The compound of the present invention has a characteristic feature that it has a substituent represented by the following formula: [0058]
(Formula Removed)
at position 7 (or at an equivalent position) of the quinoline
skeleton.
[0059]
In other words, compound of the present invention has a characteristic feature that amino group is present at position 3 of the pyrrolidinyl group; the carbon atom having this amino group bonded thereto has a substituent R3 which is not hydrogen atom; and the carbon atom at position 4 is mono- or di-substituted. That is, position 3 of the 1-pyrrolidinyl group is di-substituted by a substituent including the 3-amino group,- and position 4 is mono-or di-substituted; and accordingly, positions 3 and 4 are tri- or tetra-substituted. [0060]
This pyrrolidinyl group contains an asymmetric carbon atom, and accordingly, stereoisomerism arises as described below. First, the two species: [0061]
(Formula Removed)
are present for the position 3.
[0062]
When both R4 and R5 are not hydrogen atom (including the case when R4 and R5 together form a structure), the following structure:
[0063]
(Formula Removed)
wherein the amino group is at B-configuration is preferred.
[0064]
When either one of R4 and R5 is hydrogen atom, the following 4 types:
[0066]
[0065]
(Formula Removed)
are present. The one having structure 1 is generally more preferable than the one having structure 4, while the actual preferable form changes according to the structure of the substituent R5. All of the structures are within the scope of the present invention.
[0067]
Preferable basic skeletons for the quinolone carboxylic acid having a substituent at position 7 are as shown below.
[0068]
(Formula Removed)
[0069]
Preferable substituents at position 7 are as shown below.
[0070]
(Figure Removed)
[0071]
Accordingly, the preferable compound of the present invention is the quinolone carboxylic acid basic skeleton as mentioned above substituted with the substituent at position 7 as mentioned above (namely, the combination of the basic skeleton core and the substituent as mentioned above). In the formulae as shown above, absolute configuration at position 3 of the pyrrolidine ring substituted with the amino group is either 3R or 3S. Preferably, the compound of the present invention is stereochemically pure. [0072]
Preferred examples of the compound of the present invention is as described below.
7-[3-amino-3,4-dimethylpyrrolidine-l-yl]-6-fluoro-l-[(1R,2S)-2-fluorocyclopropyl]-1,4-dihydro-8-methyl-4-oxoquinoline-3-carboxylic acid, a salt, or a hydrate thereof,
7-[3-amino-3,4-dimethylpyrrolidine-l-yl]-6-fluoro-l-[(1R,2S)-2-fluorocyclopropyl]-1,4-dihydro-8-methoxy-4-oxoquinoline-3-carboxylic acid, a salt, or a hydrate thereof,
(3S)-10-[3-amino-3,4-dimethylpyrrolidine-l-yl]-9-fluoro-2,3-dihydro-3-methyl-7-oxo-7H-pyrido[1.2.3-de][1,4] benzoxazine-6-carboxylic acid, a salt, or a hydrate thereof,
7-[3-amino-4-ethyl-3-methylpyrrolidine-l-yl]-6-fluoro-l-[(1R,2S)-2-fluorocyclopropyl]-1,4-dihydro-8-methyl-4-oxoquinoline-3-carboxylic acid, a salt, or a hydrate thereof,
7-[3-amino-4-ethyl-3-methylpyrrolidine-l-yl]-6-fluoro-l-[(1R,2S)-2-fluorocyclopropyl]-1,4-dihydro-8-methoxy-4-oxoquinoline-3-carboxylic acid, a salt, or a hydrate thereof,
(3S)-10-[3-amino-4-ethyl-3-methylpyrrolidine-l-yl]-9-fluoro-2,3-dihydro-3-methyl-7-oxo-7H-pyrido[1.2.3-de][1,4] benzoxazine-6-carboxylic acid, a salt, or a hydrate thereof,
7-[3-amino-3-methyl-4-isopropyl pyrrolidine-1-yl]-6-fluoro-1-[(1R,2S)-2-fluorocyclopropyl]-1,4-dihydro-8-methyl-4-oxoquinoline-3-carboxylic acid, a salt, or a hydrate thereof,
7-[3-amino-3-methyl-4-isopropyl pyrrolidine-1-yl]-6-fluoro-1-[(1R,2S)-2-fluorocyclopropyl]-1,4-dihydro-8-methoxy-4-oxoquinoline-3-carboxylic acid, a salt, or a hydrate thereof,
(3S)-10-[3-amino-3-methyl-4-isopropyl pyrrolidine-1-yl]-9-fluoro-2,3-dihydro-3-methyl-7-oxo-7H-pyrido[1.2.3-de][1,4] benzoxazine-6-carboxylic acid, a salt, or a hydrate thereof,
7-[3-amino-4-cyclopropyl-3-methylpyrrolidine-l-yl]-6-fluoro-1- [ (IR,2S)-2-fluorocyclopropyl]-1,4-dihydro-8-methyl-4 -oxoquinoline-3-carboxylic acid, a salt, or a hydrate thereof,
7-[3-araino-4-cyclopropyl-3-raethylpyrrolidine-l-yl]-6-fluoro-1-[(1R,2S)-2-fluorocyclopropyl]-1,4-dihydro-8-methoxy-4-oxoquinoline-3-carboxylic acid, a salt, or a hydrate thereof,
(3S)-10-[3-amino-4-cyclopropyl-3-methylpyrrolidine-l-yl]-9-fluoro-2,3-dihydro-3-methyl-7-oxo-7H-pyrido[1.2.3-de][1,4] benzoxazine-6-carboxylic acid, a salt, or a hydrate thereof,
7-[3-amino-3-methyl-4-vinylpyrrolidine-l-yl]-6-fluoro-l-[(IR,2S)-2-fluorocyclopropyl]-1,4-dihydro-8-methyl-4-oxoquinoline-3-carboxylic acid, a salt, or a hydrate thereof,
7-[3-amino-3-methyl-4-vinylpyrrolidine-l-yl]-6-fluoro-l-[ (IR, 2S) -2-f luorocyclopropyl] -1, 4-dihydro-8-tnethoxy-4-oxoquinoline-3-carboxylic acid, a salt, or a hydrate thereof,
(3S)-10-[3-amino-3-methyl-4-vinylpyrrolidine-l-yl]-9-fluoro-2,3-dihydro-3-methyl-7-oxo-7H-pyrido[1.2.3-de][1,4] benzoxazine-6-carboxylic acid, a salt, or a hydrate thereof,
7-[3-amino-4-methylene-3-methylpyrrolidine-l-yl]-6-fluoro-l-[(IR,2S)-2-fluorocyclopropyl]-1,4-dihydro-8-methyl-4-oxoquinoline-3-carboxylic acid, a salt, or a hydrate thereof,
7-[3-amino-4-methylene-3-methylpyrrolidine-l-yl]-6-fluoro-l-[(1R,2S)-2-fluorocyclopropyl]-1,4-dihydro-8-methoxy-4-oxoquinoline-3-carboxylic acid, a salt, or a hydrate thereof,
(3S)-10-[3-amino-4-methylene-3-methylpyrrolidine-l-yl)-9-fluoro-2,3-dihydro-3-methyl-7-oxo-7H-pyrido[1.2.3-de][1,4] benzoxazine-6-carboxylic acid, a salt, or a hydrate thereof,
7-[3-amino-4-fluoromethyl-3-methylpyrrolidine-l-yl]-6-fluoro-1-[(1R,2S)-2-fluorocyclopropyl]-1,4-dihydro-8-methyl-4-oxoquinoline-3-carboxylic acid, a salt, or a hydrate thereof,
7-[3-amino-4-fluoromethyl-3-methylpyrrolidine-l-yl]-6-fluoro-1-[(IR,2S)-2-fluorocyclopropyl]-1,4-dihydro-8-methoxy-4-oxoquinoline-3-carboxylic acid, a salt, or a hydrate thereof,
(3S)-10-[3-amino-4-fluoromethyl-3-methylpyrrolidine-l-yl]-9-fluoro-2,3-dihydro-3-methyl-7-oxo-7H-pyrido[1.2.3-de][1,4] benzoxazine-6-carboxylic acid, a salt, or a hydrate thereof,
7- [ (3R)-3-amino-3-methyl-4-methylene pyrrolidine-1-yl]-6-fluoro-1-[(IR,2S)-2-fluorocyclopropyl]-8-methoxy-l,4-dihydro-4-oxoquinoline-3-carboxylic acid, a salt, or a hydrate thereof,
7-(3-amino-4-methoxy-3-methylpyrrolidine-l-yl)-6-fluoro-1-[(IR,2S)-2-fluorocyclopropyl]-8-methyl-l,4-dihydro-4-oxoquinoline-3-carboxylic acid, a salt, or a hydrate thereof,
7-(3-amino-4-methoxy-3-methylpyrrolidine-l-yl)-6-fluoro-l-[(IR,2S)-2-fluorocyclopropyl]-8-methoxy-l,4-dihydro-4-oxoquinoline-3-carboxylic acid, a salt, or a hydrate thereof,
7-[(3S,4S)-3-amino-4-fluoromethyl-3-methylpyrrolidine-l-yl]-6-fluoro-1-[(IR,2S)-2-fluoro-1-cyclopropyl]-8-methoxy-l,4-dihydro -4-oxoquinoline-3-carboxylic acid, a salt, or a hydrate thereof,
7-[(3S,4S)-3-amino-4-fluoromethyl-3-methylpyrrolidine-l-yl]-1-eyelopropyl-6-fluoro- 8-methoxy-1,4-dihydro-4 -oxoquinoline-3 -carboxylic acid, a salt, or a hydrate thereof,
7-[(3S,4S)-3-amino-4-fluoromethyl-3-methylpyrrolidine-l-yl]-6-fluoro-1-[(IR,2S)-2-fluoro-1-cyclopropyl]-8-methyl-l,4-dihydro-4-oxoquinoline-3-carboxylic acid, a salt, or a hydrate thereof,
7-[(3S,4S)-3-amino-4-fluoromethyl-3-methylpyrrolidine-l-yl]-l-cyclopropyl-6-fluoro-8-methyl-l,4-dihydro-4-oxoquinoline-3-carboxylic acid, a salt, or a hydrate thereof,
7- [ (3R)-3-amino-4-fluoro-3-methylpyrrolidine-l-yl]-6-fluoro-1-[(IR,2S)-2-fluoro-1-cyclopropyl]-8-methoxy-l,4-dihydro-4-oxoquinoline-3-carboxylic acid, a salt, or a hydrate thereof,
7-[(3R)-3-amino-4-fluoro-3-methylpyrrolidine-l-yl]-6-fluoro-1- [ (IR,2S)-2-fluoro-1-cyclopropyl]-8-methyl-l,4-dihydro-4-oxoquinoline-3-carboxylic acid, a salt, or a hydrate thereof,
7- [ (3S)-3-amino-3-fluoromethyl-4-methylpyrrolidine-l-yl]-6-fluoro-1-[(IR,2S)-2-fluoro-1-cyclopropyl]-8-methoxy-l,4-dihydro-4-oxoquinoline-3-carboxylic acid, a salt, or a hydrate thereof,
7-[(3S)-3-amino-3-fluoromethyl-4-methylpyrrolidine-l-yl]-6-fluoro-1-[(IR,2S)-2-fluoro-1-cyclopropyl]-8-methyl-l,4-dihydro-4-oxoquinoline-3-carboxylic acid, a salt, or a hydrate thereof,
7-[7-amino-7-methyl-5-azaspiro[2.4]heptane-5-yl]-6-fluoro-1-[ (IR,2S)-2-fluorocyclopropyl]-1,4-dihydro-8-methyl-4-oxoquinoline-3-carboxylic acid, a salt, or a hydrate thereof,
7-[7-amino-7-methyl-5-azaspiro[2.4]heptane-5-yl]-6-fluoro-l-[(IR,2S)-2-fluorocyclopropyl]-l,4-dihydro-8-methoxy-4-oxoquinoline-3-carboxylic acid, a salt, or a hydrate thereof,
(3S)-10-[7-amino-7-methyl-5-azaspiro[2.4]heptane-5-yl]-9-fluoro-2,3-dihydro-3-methyl-7-oxo-7H-pyrido[1.2.3-de][1,4] benzoxazine-6-carboxylic acid, a salt, or a hydrate thereof,
7-[8-amino-8-methyl-6-azaspiro[3.4]octane-5-yl]-6-fluoro-1-[(1R,2S)-2-fluorocyclopropyl]-1,4-dihydro-8-methyl-4-oxoquinoline-3-carboxylic acid, a salt, or a hydrate thereof,
7-[8-amino-8-methyl-6-azaspiro[3.4]octane-5-yl]-6-fluoro-1-[(IR,2S)-2-fluorocyclopropyl]-1,4-dihydro-8-methoxy-4-oxoquinoline-3-carboxylic acid, a salt, or a hydrate thereof,
(3S)-10- [8-amino-8-methyl-6-azaspiro[3.4]octane-5-yl]-9-fluoro-2,3-dihydro-3-methyl-7-oxo-7H-pyrido[1.2.3-de] [1,4] benzoxazine-6-carboxylic acid, a salt, or a hydrate thereof,
7-[(7S)-7-amino-7-methyl-5-azaspiro[2.4]heptane-5-yl]-1-[ (IR,2S)-2-fluorocyclopropyl]-8-methyl-l,4-dihydro-4-oxoquinoline-3-carboxylic acid, a salt, or a hydrate thereof,
7- [ (7S)-7-amino-7-methyl-5-azaspiro[2.4]heptane-5-yl]-1-cyclopropy1- 8-me thyl-1,4-dihydro-4 -oxoquinoline-3 -carboxy1i c acid, a salt, or a hydrate thereof,
7-[(7S)-7-amino-7-methyl-5-azaspiro[2.4]heptane-5-yl]-1-[(IR,2S)-2-fluorocyclopropyl]-8-methoxy-l,4-dihydro-4-oxoquinoline-3-carboxylic acid, a salt, or a hydrate thereof,
7-[(7S)-7-amino-7-methoxy-5-azaspiro[2.4]heptane-5-yl]-1-cyclopropyl-8-methyl-l,4-dihydro-4-oxoquinoline-3-carboxylic acid, a salt, or a hydrate thereof.
[0073]
Next, method for synthesizing 3-amino-3-aliphatic hydrocarbon-substituted-4-aliphatic hydrocarbon-substituted pyrrolidine derivative which is relevant with the present invention is described. Typical example of the 3-amino-3-aliphatic hydrocarbon-substituted-4-aliphatic hydrocarbon-substituted pyrrolidine derivative is 3-amino-3-aliphatic hydrocarbon-substituted-4 -aliphatic hydrocarbon-substituted pyrrolidine-1-yl group such as 3-amino-3-methyl-4-alkyl-substituted pyrrolidine-1-yl group.
[0074]
3-Amino-3-methyl-4-alkyl-substituted pyrrolidine derivative (8) which is a typical substituent compound in the present invention can be produced by synthesizing an important intermediate by 1,3-dipolar cycloaddition using 3-substituted crotonate ester (1) and azomethine ylide (2) for the reaction block, followed by hydrolysis of the ester moiety and conversion into amine. Although the inventors of the present invention selected tertiary butoxycarbonyl group for the protective group of
the amine moiety at position 3, the protective group of the amine moiety at position 3 is not limited to the tertiary butoxycarbonyl group as long as the selected protective group does not affect the subsequent reaction steps and is easily deprotected later, and a protective group which is the same as the protective group at position 1 may also be used. Synthesis of the optically active compound can be conducted, for example, by optical resolution using an appropriate intermediate, for example, by HPLC resolution using a chiral column of the appropriate intermediate, preferential crystallization of the diastereomer salt, or by bonding chiral building block to an appropriate intermediate to produce a diastereomer, separating the diastereomer by using an appropriate separation technique such as silica gel chromatography, and removing the chiral building block to produce an optically active substance. Alternatively, the optically active compound may be synthesized by using the chiral building block for the starting material .
[0075]
(Figure Removed)
[0076]
In the formula, Boc represents tertiary butoxycarbonyl group, Cbz represents benzyloxycarbonyl group, R10 represents an alkyl
group containing 1 to 6 carbon atoms, and R11 represents R4 or R5 described for the formula (I) excluding hydrogen atom.
[0077]
Step 1 is a step wherein 3-alkoxycarbonyl-3-methyl-4-substituted pyrrolidine derivative (3) is synthesized by 1,3-dipolar cycloaddition by using 3-substituted crotonate ester (1) and azomethine ylide (2) for the reaction blocks. The azomethine ylide used for producing the azomethine ylide may be produced, for example, by adding a catalytic amount of trifluoroacetic acid or a catalytic amount of silver fluoride to N-benzyl-N-(methoxymethyl) trimethylsilyl methylamine (See Journal of Organic Chemistry, vol. 52, No. 2, page 235, 1987). The reaction solvent is not particularly limited as long as it produces azomethine ylide without inhibiting the 1,3-dipolar cycloaddition. The solvent, however, is preferably dichloromethane or 1,2-dichloroethane. The reaction may be conducted at a temperature of from -20°C to the reflux temperature of the solvent, and preferably, at room temperature to the reflux temperature of the solvent.
[0078]
Step 2 is the step in which protective group at position 1 of the pyrrolidine ring is converted. This step is preferably conducted in order to enable separation and purification by extraction of the carboxylic acid derivative produced by the hydrolysis of the ester at position 3. The protective group at position 1 is preferably the one which is distinguishable in the deprotection step from the protective group of the amino group at position 3 generated in the subsequent conversion although use of the same protective group is allowable. Preferable protective group at position 1 is benzyloxycarbonyl group. The reaction for introducing this benzyloxycarbonyl is generally conducted by direct conversion by von Braun reaction using benzyl chloroformate in a solvent such as dichloromethane; by catalytic hydrolysis using a catalyst such as palladium-carbon followed by reaction with benzyl chloroformate in an appropriate solvent and in the presence of a base.
[0079]
Step 3 is the step of hydrolyzing the ester at position 3 of the pyrrolidine ring. The ester is an alkyl ester containing 1 to 6 carbon atoms, and preferably, methyl ester, ethyl ester, or tertiary butyl ester. The hydrolysis is can be conducted by any
method commonly used in the art as long as the protective group at position 1 is not affected, and typically by hydrolysis using a base or an acid. Hydrolysis of the methyl ester and the ethyl ester is conducted by reaction with an alkaline aqueous solution such as aqueous solution of sodium hydroxide, aqueous solution of potassium hydroxide, or aqueous solution of barium hydroxide in ethanol or water followed by acidification by an appropriate acid which does not affect the protective group at position 1 for separation and purification. In the case of hydrolyis of the tertiary butyl ester, the hydrolysis is conducted under acidic conditions or in the presence of an acid catalyst in an appropriate solvent in which the ester is soluble. Preferable acids include hydrochloric acid, formic acid, acetic acid, trifluoroacetic acid, and toluenesulfonic acid.
[0080]
Step 4 is the step of converting the carboxyl group at position 3 of the pyrrolidine ring to amino group. This step is generally carried out by rearrangement of carboxylic acid to amine, For example, when the rearrangement is accomplished by Curtius rearrangement, the carboxylic acid is converted to acid azide by using a reagent such as sodium azide, trimethylsilyl azide, or diphenylphosphoryl azide (DPPA) in an appropriate solvent such as toluene, and converting the acid azide to isocyanate by heating the reaction mixture, and then converting the isocyanate to amine by hydrolysis using hydrochloric acid or the like.
[0081]
Step 5 is the step of protecting the amino group at position 3 of the pyrrolidine ring. However, the subsequent steps may also be conducted without protecting the amino group. The protective group of the amino group at position 3 may be an amino protecting group commonly used in the art. However, use of a protective group which is distinguishable in the deprotection step from the protective group at position 1 is preferable. Examples include tertiary butoxycarbonyl group, acetyl group, and trifluoroacetyl group, and the preferred is tertiary butoxycarbonyl group.
[0082]
It should be noted that Step 4 and Step 5 can be
accomplished in one step when the rearrangement is conducted in an appropriate solvent. For example, Curtius rearrangement may be carried out by using diphenylphosphoryl azide (DPPA) in tertiary
butyl alcohol to produce 3-(tertiary butoxycarbonyl)aminopyrrolidine derivative. [0083]
Step 6 is the step of deprotection of position 1 of the pyrrolidine ring, and the deprotection reaction may be conducted under any conditions as long as other functional groups and configuration are not affected. Since the protective group at position 1 is benzyloxycarbonyl group with regard to the compound of the present invention, the deprotection is conducted under conditions commonly used in the art, for example, by catalytic hydrogenolysis in the presence of a catalyst such as palladium-carbon or by using ammonium formate in a protic polar solvent. When carbon - carbon unsaturated bond is present at position 4 of the pyrrolidine ring due to the presence of the substituent such as vinyl group or methylene group, the deprotection should be accomplished while maintaining the carbon - carbon unsaturated bond. Since the protective group at position 1 is
benzyloxycarbonyl group with regard to the compound of the present invention, the deprotection condition capable of maintaining the carbon - carbon unsaturated bond of the vinyl group, methylene group, or the like at position 4 of the pyrrolidine ring is provided by the method using sodium-liquid ammonia (Birch reduction conditions) in the presence of a strong acid (for example, hydrobromic acid-acetic acid, trifluoroacetic acid, and trifluoromethanesulfonic acid-trifluoroacetic acid), the method using barium hydroxide, and the like.
[0084]
Next, synthesis of pyrrolidine derivative which is typically 7-amino-7-methyl-5-azaspiro[2.4]heptane-5-yl group is described.
7-amino-7-methyl-5-azaspiro[2.4]heptane derivative (17) which is another typical compound of the present invention can be synthesized by converting ketone moiety of acetoacetate derivative into aminonitrile derivative by Strecker reaction, converting cyano group to aminomethyl group by reduction, and condensing the aminomethyl group with ester moiety (carboxylic acid unit) to produce a pyrrolidone derivative which is an important intermediate.
[0085]
Although the inventors of the present invention selected tertiary butoxycarbonyl group for the protective group of the
amine moiety at position 3, the protective group of the amine moiety at position 3 is not limited to the tertiary butoxycarbonyl group as long as the selected protective group does not inhibit the subsequent reaction steps and is easily deprotected later, and a protective group which is the same as the protective group at position 1 may also be used. Synthesis of the optically active compound can be conducted, for example, by optical resolution using an appropriate intermediate, for example, by HPLC resolution using a chiral column of the appropriate intermediate, preferential crystallization of the diastereomer salt, or by bonding chiral building block to an appropriate intermediate to produce a diastereomer, separating the diastereomer by using an appropriate separation technique such as silica gel chromatography, and removing the chiral building block to produce an optically active substance. Alternatively, the optically active compound may be synthesized by using the chiral building block for the starting material.
[0086]
(Figure Removed)
[0087]
In the formula, Boc represents tertiary butoxycarbonyl group, and R12 represents an alkyl group containing 1 to 6 carbon atoms.
[0088]
Step 7 is the step of constructing a cyclic structure at methylene moiety of the acetoacetate derivative. This step can be generally accomplished by using a 1,2-dihalogeno ethane such as dibromoethane as an alkylating agent in the presence of a base. Exemplary bases include potassium carbonate, sodium hydride, and metal sodium, and the exemplary reaction solvents include acetone and N,N-dimethylformamide. After completing the reaction, the cyclo compound may be separated and purified by distillation under a reduced pressure.
[0089]
Step 8 is the step of converting methylketone moiety to aminonitrile derivative by Strecker reaction. This Strecker reaction is conducted by reacting ammonia with a cyanating agent such as potassium cyanide optionally in the presence of ammonium chloride. The reaction conditions may be adequately selected by referring to the Strecker reaction commonly used in the amino acid synthesis.
[0090]
Step 9 is the step of reducing cyano group for conversion into methylamine. The reduction of nitrile can be generally accomplished by catalytic reduction in the presence of a catalyst in an appropriate solvent such as ethanol. Examples of the catalyst include palladium-carbon catalyst, Raney nickel, Raney cobalt, and platinum oxide. When secondary amine is produced as a byproduct in the catalytic reduction of nitrile, the reduction may be conducted in the presence of ammonia. The reduction may be carried out by a metal hydride if other functional groups in the reaction system, for example, ester group which is the typical example in the compound of the present invention is not reduced. A typical example of the metal hydride is sodium borohydride-cobalt chloride (II) . If the ester moiety is reduced, the reaction may be conducted after converting the ester moiety to a bulky ester such as tertiary butyl ester which is not reduced.
[0091]
Step 10 is the step of condensing ester moiety (carboxylic acid unit) and methylamine within the molecule to produce the
pyrrolidone derivative. When the ester moiety is methyl ester or ethyl ester, the condensation can be generally accomplished by heating the reaction solution from the room temperature in an appropriated solvent. When the ester moiety is methyl ester or ethyl ester, the pyrrolidone derivative can be directly produced from the reaction of Step 9. On the other hand, when the ester is a bulky ester such as tertiary butyl ester, the condensation is accomplished by hydrolyzing the ester by a method commonly used in the art, and then converting the hydrolyzate into the pyrrolidone derivative by using a condensing agent such as DCC.
[0092]
Step 11 is the step of protecting the amino group at position 3 of the pyrrolidine ring. However, the subsequent steps may also be conducted without protecting the amino group. The protective group of the amino group at position 3 may be an amino protecting group commonly used in the art which is stable under the reaction conditions of the subsequent step 13. However, use of a protective group which is distinguishable in the deprotection step from the protective group at position 1 is preferable. Examples include tertiary butoxycarbonyl group, acetyl group, and trifluoroacetyl group, and the preferred is tertiary butoxycarbonyl group.
[0093]
Step 12 is the step of protecting position 1 of the pyrrolidine ring. However, the subsequent steps may also be conducted without protecting the amino group. The protective group of position 1 may be an amino protecting group commonly used in the art which is stable under the reaction conditions of the subsequent step 13. However, use of a protective group which is distinguishable in the deprotection step from the amino group protective group at position 3 is preferable. The inventors of the present invention selected benzyl group for the protective group. The reaction of introducing the benzyl group is conducted by using benzyl halide in the presence of a base such as sodium hydride or potassium carbonate. The reaction solvent used may be acetone, N,N-dimethylformamide, tetrahydrofuran, or a mixture thereof.
[0094]
Step 13 is the step of reducing carbonyl group of the pyrrolidone. The reduction is conducted by using a reducing agent. Exemplary reducing agents include metal hydrides such as lithium
aluminum hydride, and sodium bis(2-methoxyethoxy) aluminum hydride, boron hydride compounds such as diborane and borane-tetrahydrofuran complex. The solvent used is typically ether solvent such as tetrahydrofuran, and the reaction may be carried
out at a temperature of -78°C to 100°C. [0095]
Step 14 is the step or deprotecting position 1 of the pyrrolidine ring, and the deprotection reaction may be conducted under any conditions as long as other functional groups and configuration are not affected. Since the protective group at position 1 is benzyl group with regard to the compound of the present invention, the deprotection is conducted under conditions commonly used in the art, for example, by catalytic hydrogenolysis in the presence of a catalyst such as palladium-carbon or by using ammonium formate in a protic polar solvent. When carbon to carbon unsaturated bond is present at position 4 of the pyrrolidine ring due to the presence of the substituent such as vinyl group or methylene group, the deprotection should be accomplished while maintaining the carbon to carbon unsaturated bond. Since the protective group at position 1 is benzyl group with regard to the compound of the present invention, the deprotection condition capable of maintaining the carbon to carbon unsaturated bond of the vinyl group, methylene group, or the like at position 4 of the pyrrolidine ring is provided, for example, by the method using sodium-liquid ammonia (Birch reduction conditions). [0096]
In the foregoing, the reactions have been described in terms of examples. Those skilled in the art will be able to find a new synthetic method by taking such reactions into consideration. The scope of the present invention is not limited by the reactions as described above. [0097]
When the compound of the present invention (I) is produced by using the thus produced Compound (8) or Compound (17), a quinolone skeleton compound represented by the following formula (18) : [0098]
(Formula I8 Removed)
[0099]
wherein R8, X1, and A are as defined above; and R91 represents hydrogen atom, dihalogenoboron, or diacyloxy boron; and X2 represents a leaving group may be reacted with Compound (8) or Compound (17).
[0100]
R91 of the quinolone skeleton compound exemplified are hydrogen atom or a boron substituent capable of producing a boron chelate. The boron substituents may be a dihalogenoboron or a diacyloxy boron. Preferable dihalogenoboron is difluoroboron (-BF2), and preferable diacyloxy boron is diacetyloxy boron [-B(OAc)2] , and these compounds can be produced by a known method.
[0101]
The production method is described by using the compound of Example 9 as an example.
[0102]
(Figure Removed)
[0103]
The target compound can be produced by dissolving the quinolone skeleton compound in an appropriate solvent and reacting Compound (8) or (17) for introducing the substituent at position 7 in the presence of a base with the quinolone skeleton compound. The amino group of the compound for introducing the substituent at
position 7 may be protected with a protective group, and exemplary protective groups other than tert-butyl oxycarbonyl (Boc) include benzyloxycarbonyl group, p-methoxy benzyloxycarbonyl group, acetyl group, methoxyacetyl group, trifluoroacetyl group, pivaloyl group, formyl group, benzoyl group, tert-butyl group, benzyl group, trimethylsilyl group, and isopropyl dimethylsilyl. Exemplary bases include carbonate, hydrogen carbonate, or hydroxide of an alkaline metal or an alkaline earth metal; a trialkylamine such as triethylamine and N,N-diisopropylethylamine; and nitrogen-containing heterocyclic group compounds such as pyridine, 1,8-diazabicycloundecene, and N-methylpiperidine, and the preferred are trialkylamines, and in particular triethylamine. The solvent used is not particularly limited as long as it does not inhibit the reaction, and preferable examples include N,N-dimethylformamide, dimethyl sulfoxide, sulfolane, acetonitrile, ethanol, dimethyl acetamide, tetrahydrofuran, and N-methyl pyrrolidone, and the more preferred are dimethyl sulfoxide or sulfolane.
[0104]
When the quinolone skeleton compound is a boron chelate compound, the target compound can be produced by cleaving the boron substituent moiety by hydrolysis, and deprotecting the protective group of the amino group. The hydrolysis of the boron substituent can be conducted under conditions commonly used in the art, for example, by reacting with a base in an alcohol solvent such as methanol and ethanol. The base is preferably triethylamine, and the reaction is preferably conducted in an ice bath. The deprotection is conducted under the conditions suitable for the protective group used, for example, by treating the hydrolyzate with concentrated hydrochloric acid. After the reaction, the reaction solution is alkalized by adding an aqueous solution of sodium hydroxide.
[0105]
Accordingly, the compounds represented by the following formulae (19) and (20) are useful as an intermediate for producing the compound (I) of the present invention.
[0106]
(Figure Removed)
[0107]
In the formulae, R11 represents a group comprising R1 as defined above (hydrogen atom, an alkyl group containing 1 to 6 carbon atoms, a cycloalkyl group containing 3 to 6 carbon atoms, or a substituted carbonyl group derived from an amino acid, a dipeptide, or a tripeptide,- the alkyl group being optionally substituted with a substituent selected from the group consisting of hydroxy group, amino group, halogen atom, an alkylthio group containing 1 to 6 carbon atoms, and an alkoxy group containing 1 to 6 carbon atoms) and the protective group of the amino acid;
R21 represents a group comprising R2 as defined above (hydrogen atom, an alkyl group containing 1 to 6 carbon atoms, or a cycloalkyl group containing 3 to 6 carbon atoms; the alkyl group being optionally substituted with a substituent selected from the group consisting of hydroxy group, amino group, halogen atom, an alkylthio group containing 1 to 6 carbon atoms, and an alkoxy group containing 1 to 6 carbon atoms) and the protective group of the amino acid; and
R3, R4, R5, R6, and R7 are as defined above. [0108]
Next, the protective group of the amino group represented by R11 and R21 is described. The protective group is not particularly limited as long the protective group is the one widely used in the art, and exemplary protective groups include alkoxycarbonyl groups such as tartiary butlxycarbonyl group, and 2,2,2-trichloroethoxycarbonyl group; aralkyloxycarbonyl groups such as benzyloxycarbonyl group, paramethoxybenzyloxycarbonyl group, and paranitrobenzyloxycarbonyl group; acyl groups such as acetyl group, methoxyacetyl group, trifluoroacetyl group, chloroacetyl group, pivaloyl group, formyl group, and benzoyl group; alkyl groups or ciralkyl groups such as tertiary butyl group, benzyl group,
paranitrobenzyl group, paramethoxybenzyl group, and triphenylmethyl group; ethers such as methoxymethyl group, tertiary butoxymethyl group, tetrahydropyranyl group, and 2,2,2-trichloroethoxymethyl group; (alkyl and/or aralkyl)-substituted silyl groups such as trimethylsilyl group, isopropyldiraethylsilyl group, tertiary butyldimethylsilyl group, tribenzylsilyl group, and tertiary butyldiphenylsilyl group. [0109]
(Figure Removed)
[0110]
In the formula R13 represents protective group of the amino group, and R11, R21, R3, R4, R5, R6 and R7 are as defined above.
[0111]
The protective group represented by R13 is not particularly limited as long the protective group is the one widely used in the art. Exemplary protective groups include alkoxycarbonyl groups such as tartiary butlxycarbonyl group, and 2,2,2-trichloroethoxycarbonyl group; aralkyloxycarbonyl groups such as benzyloxycarbonyl group, paramethoxybenzyloxycarbonyl group, and paranitrobenzyloxycarbonyl group,- acyl groups such as acetyl group, methoxyacetyl group, trifluoroacetyl group, chloroacetyl group, pivaloyl group, formyl group, and benzoyl group; alkyl groups or aralkyl groups such as tertiary butyl group, benzyl group, paranitrobenzyl group, paramethoxybenzyl group, and triphenylmethyl group,- ethers such as methoxymethyl group, tertiary butoxymethyl group, tetrahydropyranyl group, and 2,2,2-trichloroethoxymethyl group,- (alkyl and/or aralkyl)-substituted silyl groups such as trimethylsilyl group, isopropyldimethylsilyl group, tertiary butyldimethylsilyl group, tribenzylsilyl group, and tertiary butyldiphenylsilyl group.
When more than two of R11, R12 and R13 are protective groups, the actual protective groups should be chosen is able to be determined according to the knowledge of the present field of the art to be selectively removed at the synthesis of compound 19 or 20.
[0112]
The thus produced compound of Example 9 shows strong antibacterial activity as well as excellent stability and pharmacokinetics as will be evident from the Test Examples as presented below. When this compound was evaluated by X ray crystallography, absolute configuration at the part of the asymmetric carbon at position 7 (the site of the amino group substitution) of 5-azaspiro[2.4]heptane-5-yl group was (7S). This confirmed that the preferable compound is the one in which the spirobicyclic substituent at position 7 has an absolute configuration (S).
[0113]
Since the compound of the present invention has strong antibacterial activity, it can be used as a drug for human, animals, and fish, or as a preservative of agricultural chemicals and foods. The typical dose of the compound of the present invention when it is used as a human drug is 50 mg to 1 g, and more preferably 100 mg to 500 mg per day per adult. When the compound of the invention is administered to an animal, the dose is typically 1 mg to 200 mg, and more preferably 5 mg to 100 mg per day per kg weight of the animal although the dose may vary according to the size of the animal to be treated, type of the pathogenic microorganism, and seriousness of the condition. Such daily dose may be administered in a single dose or in 2 to 4 divided doses. If necessary, a dose exceeding such daily dose may be administered.
[0114]
The compound of the present invention has excellent antibacterial activity for a broad range of microorganisms causing various infections, and therefore, the present compound is capable of treating, preventing, or ameliorating the diseases caused by such pathogenic microorganisms. The compound of the present invention is effective for bacteria and the bacteria-like microorganisms including Staphylococcus, Streptococcus pyogenes, hemolytic streptococcus, enterococcus, pneumococcus,
Peptostreptococcus, Neisseria gonorrhoeas, Escherichia coli, Citrobacter, Shigella, Klebsiella pneumoniae, Enterobacter, Serratia, Proteus, Pseudomonas aeruginosa, Haemophilus influenzae, Acinetobacter, Campylobacter, and Chlamydia trachomatis.
[0115]
The diseases caused by such pathogenic microorganisms include superficial secondary infections such as folliculitis, furuncle, carbuncle, erysipelas, cellulitis, lymphangitis, whitlow, subepidermal abscess, hidradenitis, acne conglobata, infectious atheroma, perianal abscess, mastitis, and injury, burn and operative wounds; secondary infections of laryngopharyngitis, acute bronchitis, tonsillitis, chromic bronchitis, bronchiectasis, diffuse panbronchiolitis, and chronic respiratory diseases; pneumonia, pyelonephritis, cystitis, prostatitis, epididymitis, gonorrheal urethritis, nongonococcal urethritis, cholecystitis, cholangitis, shigellosis, enteritis, adnexitis, intrautarine infection, bartholinitis, blepharitis, hordeolum, dacryocystitis, rneibomianitis, corneal ulcer, middle otitis, sinusitis, periodontal inflammations, pericoronitis, jaw inflammation, peritonitis, endocarditis, sepsis, meningitis, and skin infections.
[0116]
The compound of the present invention is also effective for acid fast bacteria such as M. tuberculosis complex (Mycobacterium tuberculosis, M. bovis, and M. africans) and atypical mycobacteria (M. kansasii, M. marianum, M. scrofulaceum, M. avium, M. intracellulare, M. xenopi, M. fortuitum, and M. chelonae). The rnycobacterial infections caused by such pathogenic microorganisms are divided into three categories of tuberculosis, atypical rnycobacteriosis, and leprosy. Mycobacterial infections affect not only the lung but also thoracic cavity, trachea and bronchus, lymph nodes, by systemic dissemination, joints and bones, meninges and brain, digestive organs (intestine and liver), skin, mammary gland, eyes, auris media and throat, urinary tract, male genitalia, and female genitalia. The main organ affected by the atypical mycobacteriosis (non-tuberculous mycobacteriosis) is lung. The atypical mycobacteriosis, however, also affects by topical lymphadenitis, skin soft tissues, bones and joints, and by systemic dissemination.
[0117]
The compound of the present invention is also effective for various microorganisms causing animal infections such as Escherichia, Salmonella, Pasteurella, Haemophilus, Bordetella, Staphylococcus, and mycoplasma. Exemplary diseases include, colibacillosis, pullorum disease, avian paratyphoid, fowl cholera, infectious diarrhea, staphylococcosis, mycoplasma infection, and the like for fowls; colibacillosis., salmonellosis, pasteurellosis, hemophilosis, atrophic rhinitis, exudative epidermitis, mycoplasma infection and the like for pigs; colibacillosis, salmonellosis, hemorrhagic septicemia, mycoplasma infection, pleuropneumonia, and mastitis for cows; Escherichia coli sepsis, salmonnella infection, hemorrhagic septicemia, pyometra, cystitis, and the like for dogs,-and exudative pleurisy, cystitis, chronic rhinitis, hemophilosis, kitten's diarrhea, mycoplasma infection, and the like for cats. [0118]
The antibacterial drug containing the compound of the present invention may be prepared by selecting a dosage form appropriate for the administration route, and preparing the drug by a method commonly used in the art for producing the selected dosage form. Exemplary dosage forms for the antibacterial drug containing the compound of the present invention as its main ingredient include tablet, powder, granules, capsule, solution, syrup, elixir, and oil-base and water-base suspension. In the case of an injection, the preparation may contain a stabilizer, an antiseptic, a solubilizer, and the like and the preparation optionally supplemented with such additives may be filled in a container, and then freeze dried to produce a solid preparation to be hydrated immediately before use. The container may be filled either with a single dose or multiple doses. In the case of a solid preparation, the preparation may contain a pharmaceutically cicceptable carrier with the compound (1) , and exemplary carries include fillers, expanders, binders, disintegrants, solubilizers, wetting agents, and lubricants. The liquid preparation may be a solution, a suspension, an emulsion, or the like which may contain a suspending agent or emulsifier as an additive. [0119]
In the case of a solid preparation, the preparation may contain a pharmaceutically acceptable carrier with the active compound, and exemplary carriers include fillers, binders, disintegrants, solubilizers, wetting agents, and lubricants. The
liquid preparation may be a solution, a suspension, an emulsion, or the like which may contain a suspending agent or emulsifier as an additive. [0120]
Next, exemplary preparations are described. Preparation 1 (Capsule)
(Table Removed)
EXAMPLES
[0123]
Next, the present invention is described in further detail by referring to Reference Examples and Examples which by no means limit the scope of the present invention.
[0124]
[Reference Example 1] Ethyl (3R*,4R*)-l-benzyl-3,4-dimethylpyrrolidine-3-carboxylate
[0125]
(Figure Removed)
[0126]
To a solution of tiglic acid ethyl ester (6.41 g, 50.0 mmol) and N-benzyl-N-(methoxy-methyl)-N-trimethylsilyl methylamine
(15.35 g, 60.0 mmol) in dichloromethane (150 mL), a catalytic amount of trifluoroacetic acid was added at room temperature, and the mixture was stirred in an oil bath at 40°C for 10 hours. The reaction mixture was diluted by adding ethyl acetate (500 mL), and the solution was washed with saturated aqueous solution of sodium hydrogencarbonate (200 mL) and saturated aqueous solution of sodium chloride (200 mL), and dried with anhydrous sodium sulfate. After removing the dessicating agent by filtration, the solvent was removed by distillation under reduced pressure. The resulting residue was purified by silica gel column chromatography
(chloroform : methanol, 49:1 -» 19:1 -» 9:1) to obtain 13.73 g of crude title compound as a pale yellow oil. The crude product was used in the subsequent reaction with no further purification. [0127]
JH-NMR (400 MHz, CDC13)6 ppm: 0.96 (3H, d, J = 7
.1 Hz), 1.17 (3H, s), 1.22 (3H, t, J = 7.1 Hz), 2.16 (1H, t, J =
8.8 Hz), 2.25 (1H, d, J = 9.6 Hz), 2.61-2.67 (1H, m), 2.91 (1H, t,
J = 8.2 Hz), 3.28 (1H, d, J = 10.0 Hz), 3.53 (1H, d, J = 13.5 Hz),
3.64 (1H, d, J = 13.2 Hz), 4.11 (2H, q, J = 7.1 Hz), 7.19-7.38 (5H,
in) .
MS (ESI) m/z: 262 (M+H)+.
[0128]
[Reference Example 2]
Ethyl (3R*,4R*)-1-benzyloxycarbonyl-3,4-dimethylpyrrolidine-3 -carboxylate
[0129]
(Figure Removed)
[0130]
To a solution of ethyl (3R*,4R*)-l-benzyl-3,4-dimethylpyrrolidine-3-carboxylate (2.75 g, 10.0 mmol) in dichloromethane (30 mL), benzyl chloroformate (2.14 mL, 15.0 mmol) was added at room temperature, and the mixture was stirred at room temperature for 6 hours. Benzyl chloroformate (2.14 mL, 15.0 mmol) was also added to the mixture, and the mixture was stirred at room temperature for another 14 hours. The solvent was removed by distillation under reduced pressure, and the residue was purified by silica gel column chromatography (hexane : ethyl acetate, 9:1 —> 4:1 -» 2:1) to obtain 1.64 g of the title compound (5.37 mmol, 2 steps, 54%) as a colorless transparent oil.
[0131] ]'H-NMR (400 MHz, CDC13)8 ppm: 0.99 (1.5H, d, J
= 7.1 Hz), 1.02 (1.5H, d, J = 7.1 Hz), 1.18 (3H, s), 1.26 (3H, t, J = 7.1 Hz), 2.57-2.66 (1H, m), 3.01-3.10 (1H, m), 3.39 (0.5H, d, J = 10.7 Hz), 3.45 (0.5H, d, J = 11.0 Hz), 3.66 (1H, td, J = 11.0, 8.0 Hz), 3.77 (1H, dd, J = 10.9, 4.8 Hz), 4.11-4.19 (2H, m), 5.09-5.17 (2H, m) , 7.26-7.38 (5H, m) . MS (ESI) m/z: 306 (M+H)+.
[0132]
[Reference Example 3]
(3R*,4S*)-l-Benzyloxycarbonyl-3-(tert-butoxycarbonylamino)-3,4-dimethylpyrrolidine
[0133]
(Figure Removed)
To a solution of ethyl (3R*,4R*)-1-benzyloxycarbonyl-3,4-dimethylpyrrolidine-3-carboxylate (1.63 g, 5.34 ramol) in ethanol (16 mL), IN aqueous solution of sodium hydroxide (16.0 mL, 16.0 mraol) was added at room temperature, and the mixture was stirred at room temperature for 3.5 hours. After concentrating the solvent under reduced pressure, IN hydrochloric acid was added to the mixture for acidification, and the mixture was extracted with ethyl acetate (150 mL) . The resulting organic layer was dried with anhydrous sodium sulfate, and after removing the dessicating agent by filtration, the solvent was removed by distillation under reduced pressure to obtain crude product in the form of carboxylic acid. The crude product in the form of a carboxylic acid was used in the subsequent reaction with no further purification. [0135]
To a solution of the thus obtained crude product in the form of a carboxylic acid and triethylamine (1.488 mL, 10.68 mmol) in toluene (30 mL), diphenylphosphoryl azide (1.495 mL, 6.94 mmol) was added in an ice bath, and the mixture was stirred at room temperature for 30 minutes, and further stirred in an oil bath at
80°C for 2 hours. The reaction mixture was diluted by adding ethyl acetate (150 mL), and the solution was washed with saturated aqueous solution of sodium hydrogencarbonate (80 mL), water (80 mL), and saturated aqueous solution of sodium chloride (80 mL) in this order. The resulting organic layer was dried with anhydrous sodium sulfate, and after removing the dessicating agent by filtration, the solvent was removed by distillation under reduced pressure to obtain crude product in the form of isocyanate. The thus obtained crude product in the form of isocyanate was dissolved in 1,4-dioxane (15 mL), and after adding 6N hydrochloric acid (15 mL), the mixture was stirred for 1 hour in an oil bath at 50°C. The reaction mixture was concentrated under reduced pressure, and after azeotropically distilling with ethanol (5 times), the residue was dissolved in dichloromethane (30 mL), and to this solution at room temperature was added triethylamine (3.72 mL, 26.69 mmol), and then di-tert-butyl dicarbonate (2.33 g, 10.68 mmol) . The reaction mixture was stirred at room temperature for 3 hours, and the solvent was removed by distillation under reduced pressure. The residue was purified by silica gel column chromatography (hexane : ethyl acetate, 9:1 —» 4:1) to obtain 1.10
g (3.16 mmol, 4 steps, 59%) of the title compound as a colorless gummy solid. [0136]
:LH-NMR (400 MHz, CDCl3)5ppm: 0.94-0.98 (3H, m) , 1.24-1.26 (3H, m) ,
1.42-1.44 (9H, m), 2.44-2.62 (1H, m), 2.99-3.05 (1H, m), 3.63-3.70
(3H, m), 4.54-4.56 (1H, m), 5.08-5.17 (2H, m), 7.28-7.37 (5H, m). MS (ESI) m/z: 371 (M+Na)+. [0137]
[Reference Example 4]
(+)-(3R*,4S*)-l-Benzyloxycarbonyl-3-(tert-butoxycarbonylamino)-3,4-dimethylpyrrolidine and (-)-(3R*,45*)-l-benzyloxycarbonyl-3-
(tert-butoxycarbonylamino)-3,4-dimethylpyrrolidine
The racemic compound of (3R*,4S*)-l-benzyloxycarbonyl-3-
(tert-butoxycarbonylamino)-3,4-dimethylpyrrolidine (1.10 g, 3.16 rnmol) produced in Reference Example 3 was optically resolved by using an optically active column (CHIRALPAK AD, 20 mm diam. x 250 mm; hexane : isopropyl alcohol, 95:5; flow rate, 25 mL/minute; resolution, 30 mg per run) to produce (+)-(3R*,4S*)-1-benzyloxycarbonyl-3-(tert-butoxycarbonylamino)-3,4-dimethylpyrrolidine (528 mg; 1.52 mmol; retention time = 12.8 minutes, [a]D25.1 = +8.1° (c = 0.161, chloroform)) and (-)-
(3R*,4S*)-l-benzyloxycarbonyl-3-(tert-butoxycarbonylamino)-3,4-dimethylpyrrolidine (532 mg; 1.53 mmol; retention time = 15.8 minutes; [a]D25.1 = -6.3° (c = 0.175, chloroform)). [0138]
[Example 1]
7-[(3R*,4S*)-3-Amino-3,4-dimethylpyrrolidin-l-yl] -6-fluoro-l-
[(1R,2S)-2-fluorocyclopropyl]-8-methoxy-l,4-dihydro-4-oxoquinoline-3-carboxylic acid [0139]
(Figure Removed)
To a solution of (+)-(3R*,4S*)-l-benzyloxycarbonyl-3-(tert-butoxycarbonylamino)-3,4-dimethylpyrrolidine (490 mg, 1.406 mmol) in methanol (20 mL) was added 10% palladium-carbon catalyst (M; water content, about 50%; 147 mg), and the suspension was stirred in hydrogen atmosphere at room temperature for 2 hours. After removing the catalyst by filtration, the solvent was removed by distillation under reduced pressure to obtain crude product (314 rng, quantitative) of (3R* , 4S*) -3- (tert-butoxycarbonylamino) -3 , 4-dimethylpyrrolidine as a colorless gummy solid. [0141]
The thus obtained (3R*,4S*)-3-(tert-butoxycarbonylamino)-3,4-dimethylpyrrolidine crude product (314 mg), 6,7-difluoro-1-[(IR,2S)-2-fluorocyclopropyl]-8-methoxy-l,4-dihydro-4-oxoquinoline-3-carboxylic acid - difluoroboron complex (461 mg, 1.277 mmol), and triethylamine (0.534 mL, 3.83 mmol) were dissolved in dimethyl sulfoxide (4 mL), and the mixture was stirred in an oil bath at 35°C for 18 hours. To this reaction mixture were added a mixed solution of ethanol and water (ethanol : water = 4:1) (20 mL) and triethylamine (2 mL), and the
mixture was heated under reflux in an oil bath at 100°C for 2 hours, After concentrating the reaction mixture under reduced pressure, the residue was dissolved in ethyl acetate (150 mL), and washed with 10% aqueous solution of citric acid (80 mL), water (80 mL x 2), and saturated aqueous solution of sodium chloride (80 mL). The organic layer was dried with anhydrous sodium sulfate, and the solvent was removed by distillation under reduced pressure. The residue was dissolved in concentrated hydrochloric acid (20 mL) in an ice bath, and solution was stirred at room temperature for 10 minutes. The reaction mixture was washed with chloroform (30 mL x 3) . To the aqueous layer was added 10 mol/1 aqueous solution of sodium hydroxide in an ice bath to adjust the pH to 12.0, and the solution was further adjusted to pH 7.4 with hydrochloric acid. The solution was then extracted with a mixed solution of chloroform and methanol (chloroform : methanol = 9:1) (150 mL x 2). The organic layer was dried with anhydrous sodium sulfate, and the solvent was removed by distillation under reduced pressure. The residue was purified by recrystallization from ethanol, and the crystals were dried under reduced pressure to obtain the title compound 328 mg (0.805 mmol, 63%) as a pale yellow powder. [0142]
mp: 200-203°C.
'1 = +213.7° (c = 0.204, 0 . IN NaOH) .
(400 MHz, 0 . IN NaOD)6 ppm: 1.00 (3H, d, J = 6.6 Hz), 1.12 (3H, s), 1.55-1.70 (2H, m), 2.07 (1H, m), 3.39 (1H, d, J = 10.0 Hz), 3.48-3.69 (6H, m), 4.04 (1H, m), 4.93 (1H, dd, J = 39.1, 1.5 Hz), 7.64 (1H, d, J = 14.6 Hz), 8.47 (1H, s). Elementary analysis for C2oH23F2N3(Vl. 5H20 :
Calculated: C, 55.29; H, 6.03; F, 8.75; N, 9.67. Found: C, 55.55; H, 6.03; F, 8.45; N, 9.56. MS (FAB) m/z: 408 (M+H)+.
IR (ATR): 2974, 2935, 2879, 1722, 1614, 1572, 1537, 1502, 1456, 1390, 1356, 1323, 1271, 1207 cm"1.
[0143] [Example 2]
7-[(3R*,4S*)-3-Amino-3,4-dimethylpyrrolidin-l-yl]-6-fluoro-1-[(IR,2S)-2-fluorocyclopropyl]-8-methoxy-l,4-dihydro-4-oxoquinoline-3-carboxylic acid [0144]
(Figure Removed)
[0145]
By using a procedure similar to Example 1, (-)-(3R*,4S*)-1-benzyloxycarbonyl-3-(tert-butoxycarbonylamino)-3,4-dimethylpyrrolidine (480 mg, 1.378 mmol) was converted to (3R*,4S*)-3-(tert-butoxycarbonylamino)-3,4-dimethylpyrrolidine crude product (311 mg, quantitative), and the product was reacted with 6,7-difluoro-1-[(1R,2S)-2-fluorocyclopropyl]-8-methoxy-l,4-dihydro-4-oxoquinoline-3-carboxylic acid - difluoroboron complex (452 mg, 1.252 mmol) to obtain 348 mg (0.854 mmol, 68%) of the title compound as a pale yellow powder.
[0146] mp: 195-196°C.
25-1 = -118.3° (c = 0.224, 0.IN NaOH).
:LH-NMR (400 MHz, 0. IN NaOD)8 ppm: 1.00 (3H, d, J = 6.6 Hz), 1.14 (3H, s), 1.31-1.44 (1H, m), 1.49-1.59 (1H, m), 2.09 (1H, m), 3.39-3.57 (6H, m), 3.71 (1H, m), 3.97-4.02 (1H, m), 5.00 (1H, dm, J = 63.7 Hz), 7.63 (1H, d, J = 14.6 Hz), 8.39 (1H, d, J = 2.4 Hz). Elementary analysis for C2oH23F2N304-0 . 75H20:
Calculated: C, 57.07; H, 5.87; F, 9.03; N, 9.98.
Found: C, 57.30; H, 5.90; F, 9.13; N, 9.92. MS (FAB) m/z: 408 (M+H)+. IR (ATR): 2962, 2873, 1724, 1616, 1510, 1435, 1362, 1321, 1271 cm"
[0147]
[Reference Example 5] Methyl (3R*,4S*)-l-benzyl-3,4-dimethylpyrrolidine-3-carboxylate
[0148]
(Figure Removed)
[0149]
The procedure of Reference Example 1 was repeated by using methyl angelate (12.01 mL, 100.0 mmol) and N-benzyl-N-(n-butoxy methyl)-N-trimethylsilyl methylamine (36.0 g, 128.9 mmol) to obtain 12.28 g of the crude title compound as a yellow oil. The thus obtained crude product was used in the subsequent reaction with no further purification. MS (ESI) m/z: 248(M+H)+.
[0150]
[Reference Example 6]
Methyl (3R*,4S*)-l-benzyloxycarbonyl-3,4-dimethylpyrrolidine-3-carboxylate
[0151]
(Figure Removed)
[0152]
The procedure of Reference Example 2 was repeated by using the thus synthesized methyl (3R*,4S*)-l-benzyl-3,4-dimethylpyrrolidine-3-carboxylate crude product (12.28 g) and benzyl chloroformate (21.3 mL, 149.3 mmol) to obtain 4.23 g (14.52 mmol, 2 steps, 15%) of the title compound as a colorless oil.
[0153]
XH-NMR (400 MHz, CDC13)8 ppm: 0.94 (1.5H, d, J = 6.8 Hz), 0.96 (1.5H, d, J = 6.7 Hz), 1.30 (1.5H, s), 1.31 (1.5H, s), 2.14 (1H,
m) , 3.16-3.28 (2H, m) , 3.64-3.71 (4H, m), 3.92 (1H, dd, J = 14.6,
11.5 Hz), 5.16 (2H, m), 7.26-7.37 (5H, m).
MS (ESI) m/z: 292 (M+H)+.
[0154]
[Reference Example 7] (3R*,4R*)-l-Benzyloxycarbonyl-3-(tert-butoxycarbonylamino)-3,4-
dimethylpyrrolidine [0155]
[0156]
To a solution of methyl (3R*, 4S*)-l-benzyloxycarbonyl-3,4-dimethylpyrrolidine-3-carboxylate (4.23 g, 14.52 mmol) in methanol (88 mL), IN aqueous solution of sodium hydroxide (44.0 mL, 44.0 mmol) was added at room temperature, and the mixture was stirred at room temperature for 5 hours, and in an oil bath at 50°C for another 19 hours. To the mixture was added sodium hydroxide (1.742 g, 43.6 mmol), and this mixture was also stirred in an oil bath at 50°C for 8 hours. After concentrating the solvent under reduced pressure, concentrated hydrochloric acid was added to the concentrate in an ice bath for acidification, and the solution was

(Figure Removed)
[0208]
By using a procedure similar to Example 1, (-) -(3R*,45*)-1-benzyloxycarbonyl-3 -(tert-butoxycarbonylamino)-4 -fluoromethyl-3 -methylpyrrolidine (303 mg, 0.827 mmol) was converted to crude (3R*,4S*)-3 -(tert-butoxycarbonylamino)-4-fluoromethyl-3 -methylpyrrolidine, and the product was reacted with 6,7-difluoro-

X ray structural analysis was conducted to determine the configuration of position 7 of this compound. The results were as shown in FIG. 3.
After collecting the data, initial phase was resolved by direct method, and refined by full matrix least square method. In the refinement, anisotropic thermal parameters were used for the non-hydrogen atoms, and hydrogen atoms were placed in calculated positions in the coordinates. This compound has two asymmetric carbon atoms, and absolute configuration of one asymmetric carbon atom was known. The absolute configuration of the other asymmetric carbon atom, therefore, was determined based on the absolute configuration of the known asymmetric carbon atom. The results are shown in FIG. 1. The configuration of the position 7 of the title compound was thus determined to be (S). The configuration of a series of compounds produced by using this compound as an intermediate was also determined.
[0677]
[Reference Example 108]
(7S)-7-Methyl-4-oxo-5-[(1R)-phenylethyl]-5-azaspiro[2.4]heptane-7-carboxylic acid
[0678]
(Figure Removed)
[0679]
To a solution of tertiary butyl (7S)-7-methyl-4-oxo-5-[(1R)-phenylethyl]-5-azaspiro[2.4]heptane-7-carboxylate (24.5 g, 74.4 mmol) in dichloromethane (120 mL), trifluoroacetic acid (120 mL) was added dropwise in an ice bath, and the mixture was stirred for
2 hours. The reaction mixture was dried under reduced pressure,
and after adding toluene (20 mL) to the residue, the mixture was
dried under reduced pressure. The residue was dissolved in 1 mol/1
aqueous solution of sodium hydroxide (300 mL), and the aqueous
solution was washed with ethyl acetate (350 mL). To the aqueous
layer was added concentrated hydrochloric acid (25 mL) to pH 2 to
3 in an ice bath, and the mixture was extracted with chloroform
(300 mL x 2) . The organic layer was washed with water (200 mL) and saturated aqueous solution of sodium chloride (100 mL), and dried with anhydrous sodium sulfate, and the solvent was removed by distillation under reduced pressure. Toluene (20 mL) was added to the residue, and the mixture was dried under reduced pressure. The residue was suspended in chloroform (20 mL), and hexane (200 mL) was added for recrystallization. The precipitated solid was washed with hexane (100 mL), and dried under reduced pressure to obtain 20.48 g (quantitative) of the title compound as a white solid. The product was used in the subsequent step with no further purification. [0680]
]'H-NMR (400 MHz, CDCl3)Sppm: 0.78-0.83 (1H, m) , 0.90-0.95 (1H, ra) , 1.08-1.18 (2H, m), 1.24 (3H, s), 1.55 (3H, d, J = 7.3 Hz), 3.11 (1H, d, J = 10.0 Hz), 3.55 (1H, d, J = 10.0 Hz), 5.52 (1H, q, J = 7.1 Hz), 7.28-7.32 (5H, m). MS (ESI) m/z: 274 (M+H)+.
[0681]
[Reference Example 109]
(75)-7-Amino-7-methyl-4-oxo-5-[(1R)-phenylethyl]-5-azaspiro[2.4]heptane
[0682]
(Figure Removed)
[0683]
To a solution of (7S)-7-methyl-4-oxo-5-[(1R)-phenylethyl]-5-azaspiro[2.4]heptane-7-carboxylic acid (20.4 g, 74.4 mmol) and diphenylphosphoric acid azide (17.6 mL, 81.8 mmol) in toluene (200 mL), triethylamine (20.7 mL, 149 mmol) was added, and the mixture was stirred in an oil bath at 125°C for 1 hour. The reaction mixture was concentrated under reduced pressure to obtain the crude product in the form of an isocyanate.
After dissolving the crude product in the form of an isocyanate in 1,4-dioxane (180 mL), water (90 mL) and concentrated hydrochloric acid (90 mL) were added to the mixture. The mixture
was stirred in an oil bath at 50°C for 1 hour, and water (200 mL) was added to the reaction mixture. After washing with ethyl acetate (200 mL), 10 mol/1 aqueous solution of sodium hydroxide (170 mL) was added to the aqueous layer to pH 9 to 10, and the solution was extracted with toluene (200 mL x 2). The organic layer was washed with saturated aqueous solution of sodium chloride (100 mL), and dried with anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure to obtain 15.8 g (64.7 mmol) of the title compound as a pale yellow oily product. The product was used in the subsequent step with no further purification. [0684]
^-NMR (400 MHz, CDCl3)6ppm: 0.72-0.78 (2H, m), 0.99-1.10 (2H, m) , 1.08 (3H, s) , 1.53 (3H, d, J = 7.4 Hz), 2.82 (1H, d, J = 9.6 Hz), 3.27 (1H, d, J = 9.6 Hz), 5.56 (1H, q, J = 7.1 Hz), 7.14-7.37 (5H, m) .
[0685]
[Reference Example 110]
(7S)-7-(Tertiary butoxycarbonylamino)-7-methyl-5-[(IR)-phenylethyl]-5-azaspiro[2.4]heptane [0686]
(Figure Removed)
[0687]
The (7S)-7-amino-7-methyl-4-oxo-5-[(IR)-phenylethyl]-5-azaspiro[2.4]heptane (15.8 g, 64.7 mmol) was dissolved in toluene (82 mL), and a solution of 65% (by weight) solution of sodium bis(2-methoxyethoxy)aluminum hydride in toluene slution (77.6 mL, 259 mmol) in toluene (6 mL) was added dropwise in 15 minutes in an
ice bath so that the inner temperature did not exceed 70°C, and the mixture was stirred at room temperature for 10 minutes. The reaction mixture was cooled in an ice bath, and 25% (by weight) aqueous solution of sodium hydroxide (100 mL) was added dropwise. After quenching the solution, the solution was extracted with
toluene (135 mL) . The organic layer was washed with saturated aqueous solution of sodium chloride (100 mL), and di-tert-butyl dicarbonate (15.6 g, 71.2 mmol) was added. The reaction mixture was stirred at room temperature for 3 hours, and the solvent was removed by distillation under reduced pressure. The residue was purified by silica gel column chromatography (elusion by hexane : ethyl acetate, 8:1 -» 4:1 -> 1:1) to obtain 18.0 g (73%) of the title compound as a colorless transparent syrup substance. [0688]
^-NMR (400 MHz, CDCl3)8ppm: 0.37-0.49 (2H, m) , 0.62-0.68 (1H, m) , 0.77-0.82 (1H, m), 1.20 (3H, s), 1.32 (3H, d, J = 6.6 Hz), 1.44
(9H, s), 2.46 (2H, dd, J = 33.2, 9.3 Hz), 2.68 (1H, d, J = 8.8 Hz), 3.27 (1H, q, J = 6.6 Hz), 3.31-3.34 (1H, m), 4.71 (1H, s), 7.19-7.34 (5H, m).
MS (ESI) m/z: 331 (M+H)+. [0689]
[Reference Example 111]
(7S)-7-(Tertiary butoxycarbonylamlno)-7-methyl-5-azaspiro[2.4]heptane [0690]
(Figure Removed)
[0691]
To a solution of (7S)-7-(tertiary butoxycarbonylamino)-7-methyl-5-[(IR)-phenylethyl]-5-azaspiro[2.4]heptane (18.0 g, 54.5 mmol) in methanol (180 mL) was added 10% palladium-carbon catalyst (water content, 52.8%; 9.00 g), and the mixture was stirred at room temperature for 18 hours in hydrogen gas atmosphere, and in an oil bath at 40°C for 5.5 hours. After removing the catalyst, the solvent was dried under reduced pressure to obtain 13.4 g (quantitative) of the crude target compound as a white solid.
[0692]
XH-NMR (400 MHz, CDCl3)5ppm: 0.38-0.43 (1H, m) , 0.54-0.61 (2H, m) , 0.74-0.80 (1H, m), 1.08 (3H, s), 1.44 (9H, s), 2.75 (1H, d, J =
7.6 Hz), 2.78 (1H, d, J = 7.1 Hz), 3.13 (1H, d, J = 11.5 Hz), 3.73-3.77 (1H, m), 4.45 (1H, s). MS (ESI) m/z: 227 (M+H)+.
[0693]
[Reference Example 112]
7- [ (75)-7-Amino-7-methyl-5-azaspiro[2.4]heptan-5-yl]-6-fluoro-1-[ (1R,2S)-2-fluorocyclopropyl]-8-methoxy-l,4-dihydro-4-oxoquinoline-3-carboxylic acid
[0694]
(Figure Removed)
[0695]
(7S)-7-(tertiary butoxycarbonylamino)-7-methyl-5-
azaspiro[2.4]heptane (13.4 g, 54.5 mmol), 6,7-difluoro-1-[(1R,2S)-2-fluorocyclopropyl]-8-methoxy-l,4-dihydro-4-oxoquinoline-3-carboxylic acid - difluoroborane complex (17.9 g, 49.5 mmol), and triethylamine (8.97 mL, 64.4 mmol) were dissolved in dimethyl sulfoxide (52 mL), and the mixture was stirred in an oil bath at 40°C for 17 hours. The reaction mixture was poured into cold water
(1000 mL), and the precipitated solid was collected by filtration. To this solid were added a mixed solution of ethanol and water
(ethanol : water, 5:1) (180 mL) and triethylamine (15 mL), and the mixture was heated under reflux for 1.5 hours. The reaction mixture was dried under reduced pressure, and the residue was dissolved in ethyl acetate (150 mL x 2) and washed with 10% aqueous solution of citric acid (200 mL), water (200 mL), and saturated aqueous solution of sodium chloride (100 mL). The organic layer was dried with anhydrous sodium sulfate, and the solvent was removed by distillation under reduced pressure. The residue was dissolved in a mixed solution of chloroform and methanol (chloroform : methanol, 9:1) (100 mL), and after adding silica gel (10 g), the mixture was stirred for 1 hour. After removing silica gel by filtration, the mixture was washed with a mixed solution of chloroform and methanol (chloroform : methanol, 9:1) (50 mL x 2), and the filtrates were combined and concentrated
to dryness. The residue was dissolved in concentrated hydrochloric acid (200 mL) in an ice bath, and stirred at room temperature for 30 minutes. The reaction mixture was washed with chloroform (400 mL x 5) . In an ice bath, 10 mol/1 aqueous solution of sodium hydroxide was added to the aqueous layer to adjust the pH to 11.8, and the pH was further adjusted to 7.4 by adding hydrochloric acid. The solution was extracted by adding chloroform (1000 mL x 3). The organic layer was dried with anhydrous sodium sulfate, and the solvent was removed by distillation under reduced pressure. The residue was purified by recrystallization from ethanol, and the crystals were dried under reduced pressure to obtain 18.5 g (79%) of the title compound as a pale pink powder.
1H-NMR and other data from instrumental analysis of this product were fully consistent with the data of the compound produced in Example 9. In other words, of the quinolone derivatives having 7-amino-7-methyl-5-azaspiro[2.4]heptane-5-yl group, the quinolone derivative described in Example 9 which is a compound with high activity has a 5-azaspiro[2.4]heptane-5-yl group in which the stereochemical configuration at position 7 is (7S) .
[0696] [Test Example 1]
The compounds of the present invention were evaluated for their antibacterial activity according to the standard method defined by Japanese Society of Chemotherapy, and the results are shown in MIC (jig/ml) in the table, below. In the table, MIC value is also shown for moxifloxacin (MFLX), Comparative compound 1 which is the compound described in Japanese Patent Application Laid-Open No. 2-231475 (Patent Document 2), levofloxacin (LVFX), gatifloxacin (GTFX), and ciprofloxacin (CPFX), in addition to the compound of the present invention. (The structure below shows only the core structure). S. aureus, 87037 is LVFX-resistant MRSA and S. pneumoniae, J24 is penicillin-intermediate resistant bacteria.
[0697]

(Figure Removed)
[0698] [Table 1]
(Table Removed)
[0699]
[Test Example 2]
The compounds produced in Examples 2, 3, and 9 of the present invention were evaluated by mouse bone marrow micronucleus test by using 5 animals per group of 6-week-old Slc:ddY male mice, and the compounds diluted with 0.1 mol/1 NaOH/physiological saline. The control was 0.1 mol/1 NaOH/physiological saline solvent, and the positive control was cyclophosphamide (cyclophoshamide, CP) dissolved and diluted in physiological saline. All samples were sterilized by filtering through Milex GS filter (0.22 |xm) . Each solution was intravenously administered at a dose of 10 mL/kg in single dose at an administration rate of 0.2 mL/min.
Bone marrow cells were collected from thigh bone at 24 hours after the administration, and smear preparation was prepared. After staining with acridine orange, 1000 polychromatic erythrocytes per animal were observed under fluorescence microscope to count frequency of micrronucleated polychromatic erythrocyte and ratio of the orthochromatic erythrocytes to the polychromatic erythrocyte in 1000 erythrocytes. [0700]
No significant difference in the micronucleus induction rate with the control was found in all of the administration groups of the compound of Example 2 at a dose of 50 and 100 mg/kg, the administration groups of the compound of Example 3 :at a dose of 100 and 150 mg/kg, and the administration group of the compound of Example 9 at a dose of 50, 100, and 150 mg/kg, and the evaluation result was negative. In other words, the compounds of the present invention has very weak micronucleus induction in the in vivo mouse bone marrow micronucleus test used in evaluating genotoxicity, and therefore, highly safe. [0701]
[Test Example 3]
The compounds described in Examples 2, 3, and 9 of the present invention were evaluated for concentration in blood and other organs after the administration by the procedure as described below. The Comparative compound was also evaluated by the same procedure. [0702]

The test substance was orally administered to fasted rats (7 week old male Crj:CD IGS rats purchased from Charles River Laboratories Japan, Inc.) at a dose of 5 mg/kg.
Animals of absorption test group (3 animals per group) were sacrificed by bleeding under etherization at 0.25, 0.5, 1, 2, 4, and 8 hours after the drug administration, and blood, lever, kidney, and lung were collected. The blood was centrifuged (3000 rpm x 15 minutes, 4°C) after coagulation to collect serum. Tissue was homogenized after adding 3 to 5 mL of 0.1 mol/1 phosphate buffer (pH 7.0), and the supernatant was collected from the homogenate (3000 rpm x 15 minutes, 4°C) .
Animals of excretion test group (3 animals per group) were placed in a metabolic cage, and the urine of 0 to 4 hours and 4 to 24 hours after the administration was collected in a water-cooled container. Simultaneously with the collection of the urine, the cage was also washed with about 15 mL of 0.1 mol/1 phosphate buffer (pH 7.0) to collect the urine attached to the cage. For evaluation of conjugates such as glucuronide, the collected sample was also aliquoted and hydrolyzed with an equal amount of 1 mol/1 aqueous solution of sodium hydroxide, and the hydrolysate was neutralized with 0.5 mol/1 hydrochloric acid and measured for its concentration. The concentration was measured by LC-MS/MS method. [0703]
Pharmacokinetic parameters of the each drug in rat were calculated by from the time course of the average concentration by using pharmacokinetic analysis software PSAG-CP (AS Medica Inc.) in a manner not dependent on the model animal. [0704] [Table 2]
Pharmacokinetics in rat
(Table Removed)
[0705]
By repeating the procedure used for the rats, the compound of Example 9, comparative compound 1, and MFLX were evaluated for cynomolgus monkey by using fasted female cynomolgus monkey (3 animals per group) which had been administered with a dose of 5 mg/kg in single dose, and measuring intact compounds in serum and excreted urine. The measurement was conducted by LC-MS/MS method. [0706] [Table 3]
(Table Removed)

[0707]
As apparent from the data of the serum concentration, the tissue concentration, and AUC, the compound of the present invention, and in particular, the compound of Example 9 exhibited a serum concentration and a tissue concentration by oral administration which is about 2 times higher, and an AUC value which is 1.5 to 2 times higher than those of the Comparative compound 1 indicating the excellent oral absorptivity and tissue penetration of the present compound. Excretion rate in urine was about 1.5 times higher than that of the Comparative compound 1 indicating the excellent urine excretion. The data was even superior in cynomolgus monkey, and the blood penetration was about 2.5 times higher, and the urine excretion rate was more than 2 times higher than those of the Comparative compound 1.
The compound of Example 9 and MFLX exhibited similar pharmakokinetics in rat and cynomolgus monkey. However, the compound of Example 9 exhibited significantly superior blood penetration and urine excretion in cynomolgus monkey, clearly indicating that the compound of Example 9 exhibits excellent
pharmacokinetic properties not only in single species but in more than one animal species.
[0708] [Test Example 4]
The potential convulsant activity upon intracisternal administration to mouse was evaluated according to the method of Ueda et al. (Eur. J. Pharmacol., 1979, 56,265-268). The test substance was intracisternally administered to male Slc:ddy mice (6 animals per group ), and the convulsion and death were monitored for each cage until 30 minutes after the administration. The test substance was dissolved in 5 j^l of 1% aqueous solution of lactic acid, and the dose was 5, 15, or 50 jug per animal.
[0709] [Table 4]

Number of mice which showed convulsion
(Figure Removed)
[0710]
The potential convulsant activity upon intracisternal administration to mouse was also evaluated for the concomitant and administration with 4-biphenyl acetic acid (BPAA: an active metabolite of fenbufen) and in the absence of such concomitant administration. The evaluation was conducted by using 4 week old male SlcrddY mice (6 animals per group) and intracisternally
administering the test substance at a dose of 5 |ig/5 j^L/mouse (solvent, 0.5% lactic acid). Monitoring of the animals for the convulsion and death was started immediately after the administration and continued to 30 minutes after the administration. When used concomitantly with the BPAA, BPAA was suspended in 5% CMC, and 400 mg/kg was orally administered at a solution amount of 10 mL/kg, and the test substance was intracisternally administered 30 minutes after the BPAA. [0711] [Table 5]
(Table Removed)
[0712]
The compound of the present invention exhibited a convulsion inducing frequency at a high dose which is higher that of the comparative compound I but lower than ciprofloxacin (CPFX) which are widely used in clinical practice indicating weaker convulsion inducing activity, hence, higher safety compared to CPFX. The test
of concomitant administration with the biphenyl acetic acid which is the model of the concomitant administration with the fenbufen also indicated the excellent safety of the present compound since no case of convulsion or death was found for the compound of Example 9 whereas convulsion and death were noted in the administration of ciprofloxacin.
[0713] [Test Example 5]
Guinea pig maximization test (GPMT) which is a widely accepted model for delayed antigenicity was conducted according to the method of Mugnusson et al. (J. invest. Dermatol., 52, 1969) by using a cutaneous sensitization concentration of 1% and a patch sensitization and induction concentration of 10%. At day 1, the animal was sensitized by cutaneously administering the test substance (the quinolone compounds and the control: vehicle, vaseline) (1% solution in physiological saline + FCA emulsion) at the back of the head of the shaved guinea pigs (7 week old male Slc:Hertley). At day 7, lauryl sodium sulfate (SLC) was applied for stimulus (adjuvant treatment), and on the next day, the test substance coated on a wax paper was patched onto the shaved skin to for sealed sensitization, and after 48 hours (at day 10), the waxed paper was removed. The skin reaction was observed upon the removal. On day 22, the test substance (10%) was patched onto the anterior side of the body for induction, and the induction patching was removed after 24 hours. On the next day (at day 24) and the next day (at day 25), the skin reaction was evaluated according to the description of the document as mentioned above. Erythema and edema were scored, and the case with the total score of 2 or higher was evaluated to be positive with the maximum of the score being 7.
[0714] [Table 6]
(Table Removed)
[0715]
The compound of Example 9 was confirmed to be GPMT negative (score, 0) . On the other hand, Comparative compound 1 exhibited a score of 6.8, which is almost the highest score. In the meanwhile, gemifloxacin (gemifloxacin mesylate; product name, FACTIVE(TM)) which recently became commercially available in the U.S. has been reported in the phase 3 clinical trial which was conducted for community-acquired pneumonia and acute exacerbation of chromic
bronchitis that it frequently develops the side effect of rash and the rash development is frequently found after day 7 of the repeated administration. This gemifloxacin was also confirmed to be GPMT positive with the score of 6.8 which is almost the highest score as was the case Comparative compound 1. Since the gemifloxacin that had been reported to induce rash development was GPMT positive, the GPMT negative compound of the present invention was indicated to have a reduced risk of rash development. [0716] [Test Example 6]
Measurement of hERG-K+ channel blocking effect which is an in vitro standard evaluation system for cardiotoxicity (an abnormality inducing lethal arrhythmia which is found by an electrocardiogram and which is observed as prolonged QT or QTc interval) which has recently been reported as a side effect of quinolone antibacterial agent was conducted by the method described in Biophysical Journal, vol. 74, page 230, 1998. [0717] [Table 7]
(Table Removed)
[0718] [Table 8]
(Table Removed)
[0719]
The hERG-K+ channel blocking effect was confirmed to be markedly weak in the compound of the present invention compared to MFLX and GTFX with clinical reports for the action of elongating the QT or QTc interval, and Comparative compound 1.
[0720] [Test Example 7]
Mechanism-based inhibition (MBI) of CYP3A4 was evaluated by using inhibition of hydroxylation at position 1 of midazolam. While Comparative compound 1 exhibited significant inhibition in a manner dependent on the preincubation time and the drug concentration, the compound of Example 9 exhibited weak inhibition even when used at a high concentration. [0721]
Several mechanisms are involved in the drug interaction by the CYP inhibition, and among such inhibition, the inhibition by generation of a stable complex of the metabolite of the concomitant drug with the CYP, and the inhibition by the inactivation of the CYP by the binding of the metabolite of the concomitant drug with the hem- or apo-protein moiety are irreversible, and such irreversible inhibition may last for a substantial period after stopping the administration of the concomitant drug and may induce a serious side effect. Such irreversible inhibition is called a "metabolism-based inhibition". Of the CYP molecular species involved in the drug metabolism in human, CYP3A4 is involved in the metabolism of 50% or higher of the drug in clinical use. (Non-patent document: Drug Metabolism, 2nd ed., Tokyo Kagaku Dojin, 2000). Accordingly, a reagent which exhibits MBI action for CYP3A4 can be regarded as a substance having a high risk of being involved in a drug interaction.
For example, clarithromycin which is frequently used as a therapeutic drug for bacterial respiratory infection is known to exhibit MBI action for CYP3A4 (see the document as mentioned above), and use of clarithromycin concomitantly with terfenadine (an antihistamine) is conterindicated since such concomitant administration results in the increased blood concentration of the terfenadine due to the inhibition of the terfenadine metabolism by CYP3A4 caused by the clarithromycin, and prolonged QT interval in the electrocardiogram, venticular arrhythmia, and occasionally, cardiac arrest are found. However, the compound of Example 9 was
revealed to have a clearly weaker MBI even when tested at a high concentration (with a significant safe margin compared to the postulated concentration in clinical use). Therefore, the compound of the present invention is estimated to be associated with a greatly reduced risk of developing clinical side effects by the drug interaction based on the MBI action for CYP3A4.
[0722] [Test Example 8]
Mouse local lung infection model by penicillin resistant Streptococcus pneumoniae (PRSP) was used to compare the therapeutic effect of the compound of Example 9 and Comparative compound 1.
PRSP strain 033806 that had been anaerobically cultivated in Todd Hewitt Broth was nasally administered to Male CBA/JNCrlj mice (3 to 4 week old; Charles River Laboratories Japan, Inc.; 4 animals per group) under anesthesia with ketamine-xylazine mixture. Compound of Example 9 and comparative compound 1 were orally administered to this injection model, respectively, at a dose shown in FIG. 2 (25, 50, and 100 mg/kg/day) at 2 and 8 hours after the infection (treated for only 1 day at a daily dose of 50, 100, or 200 mg/kg/day). Untreated control group was administered with distilled water for injection.
Number of the bacteria in the lung was measured immediately before the drug administration for the untreated group (2 hours after the infection, indicated in the drawing as "Pre-control"), and on the neaxt day of the drug administration for the untreated group (the next day of the infection, indicated as "Post-control") and treated groups for use as an index of therapeutic effect. [0723]
As evident from FIG. 2, while the in vivo antibacterial activity of the compound of Example 9 for the test bacteria was about 1/4 of the comparative compound 1, no significant difference was found between the therapeutic effect of the compound of Example 9 and that of the comparative compound 1 in the oral administration to the mouse local lung infection model by PRSP for all groups administered with the same dose.
[0724]
[Test Example 9] Therapeutic effect in rat simple cystitis model (E. coli)
Infection model: Rats (7 week old male Crl:CD(SD) (IGS) rats, Charles River Laboratories Japan, Inc., 4 animals per group) that had been deprived of water from the previous day were anesthetized with ketamine-xylazine mixture, and E. coli strain E77156 was transurethrally inoculated (1.2 x 107 CFU/rat) in the bladder. After the administration, urethral orifice was closed for 2 hours to thereby prevent discharge of the bacterial solution, and feeding of the water was started simultaneously with the termination of closure.
Drug administration: Compound of Example 9 and Comparative Compound 1 were orally administered respectively at a dose of 5, 20, or 80 mg/kg on the next day of the infection in a single dose. Evaluation of the effectiveness: Number of the bacteria in the bladder was measured immediately before the drug administration and on the next day of the drug administration (2 days after the infection) for the untreated group, and on the next day of the drug administration for the treated groups for use as an index of therapeutic effect.
[0725]
Results: A significant decrease in the number of bacteria was found only for the compound of Example 9 when the dose was 20 or 80 mg/kg/day. The therapeutic effect of this compound for the group with the dose of 5 mg/kg/day was significantly stronger than the Comparative Compound 1. Accordingly, the compound of Example 9 was demonstrated to be a compound which is capable of realizing therapeutic effects superior to those of the Comparative Compound 1 (FIG. 4) .
[0726] [Test Example 10]
The compounds of the present invention were evaluated for their anti-Mycobacterium tuberculosis activity according to the standard method defined by Japanese Society of Chemotherapy (Journal of Japanese Society of Chemotherapy, vol. 29, pages 76 to 79, 1981), and the results are shown in MIC (jag/ml) in the Tables 9 and 10, below. The compounds of the present invention exhibited superior antibacterial activity for Mycobacterium tuberculosis.

We Claim:
1. A quinolone derivative having a 3-aminopyrrolidinyl group which is tetra- substituted at
position 3 and 4 in that it is represented by following formula (I):
(Formula Removed)
or a salt of the kind such as herein described or a hydrate thereof, wherein
R1 and R2 each represents hydrogen atom;
R3 represents an alkyl group containing 1 to 6 carbon atoms, which being optionally
substituted with halogen atom;
R4 and R5 together represent (a) a 3- to 6-membered cyclic structure including the carbon
atom shared by R4 and R5 to form a spirocyclic structure with the pyrrolidine ring; or (b)
exomethylene group bonding to the pyrrolidine ring by double bond;
R6 and R7, each represents hydrogen atom;
R8 represents a halogen-substituted cycloalkyl group containing 3 to 6 carbon atoms;
R9 represents hydrogen atom or an alkyl group containing 1 to 6 carbon atoms;
X1 represents hydrogen atom or a halogen atom; and
A represents a moiety represented by formula (II):
(Formula Removed)
wherein X2 represents an alkyl group containing 1 to 6 carbon atoms or an alkoxy group containing 1 to 6 carbon atoms.
2. The compound, or a salt or a hydrate thereof as claimed in claim 1, wherein the
compound represented by the formula (I) is a compound represented by the following
formula:

(Formula Removed)
wherein R1, R2, R3, R4, R5, R6, R7, R8, R9, X1, and A are as defined above.
3. The compound, or a salt or a hydrate thereof as claimed in claim 1 or 2, wherein R3 in formula (I) is methyl group or ethyl group.
4. The compound, or a salt or a hydrate thereof as claimed in claim 1 or 2, wherein R3 in formula (I) is methyl group.
5. The compound, or a salt or a hydrate thereof as claimed in any one of claims 1 to 4, wherein R and R in formula (I) together form cyclopropane ring or cyclobutane ring including the carbon atom shared by R4 and R5 to form a spirocyclic structure.
6. The compound, or a salt or a hydrate thereof as claimed in any one of claims 1 to 4, wherein R4 and R5 in formula (I) together form cyclopropane ring including the carbon atom shared by R4 and R5 to form a spirocyclic structure.
7. The compound, or a salt or a hydrate thereof as claimed in any one of claims 1 to 4, wherein R4 and R5 in formula (I) together form an exomethylene group.
8. The compound, or a salt or a hydrate thereof as claimed in any one of claims 1 to 7, wherein X1 in formula (I) is fluorine atom.
9. The compound, or a salt or a hydrate thereof as claimed in any one of claims 1 to 8, wherein X2 in formula (II) is methyl group or methoxy group.
10. The compound, or a salt or a hydrate thereof as claimed in any one of claims 1 to 9, wherein R8 in formula (I) is a l,2-cis-2halogenocyclopropyl group.
11. The compound, or a salt or a hydrate thereof as claimed in any one of claims 1 to 10, wherein R8 in formula (I) is a stereochemically pure l,2-cis-2-halogenocyclopropyl group.
12. The compound, or a salt or a hydrate thereof as claimed in claim 11, wherein the 1,2-cis-2-halogenocyclopropyl group which is R8 in formula (I) is (lR,2S)-2-halogenocyclopropyl group.

13. The compound, or a salt or a hydrate thereof as claimed in claim 12, wherein the (1R,2S)-2-halogenocyclopropyl group which is R8 in formula (I) is (lR,2S)-2-fluorocyclopropyl group.
14. The compound, or a salt or a hydrate thereof as claimed in any one of claims 1 to 13, wherein R9 in formula (I) is hydrogen atom.
15. The compound, or a salt or a hydrate thereof as claimed in any one of claims 1 to 14, wherein the compound of formula (I) is a stereochemically pure compound.
16. A compound as claimed in claim 1 selected from 7-[3-amino-4-methylene-3-methylpyrrolidine-1 -yl]-6-fluoro-1 -[(lR,2S)-2-fluorocyclopropyl]-l,4-dihydro-8-methyl-4-oxoquinoline-3-carboxylic acid, or a salt or a hydrate thereof;
7-[3-amino-4-methylene-3-methylpyrrolidine-1 -yl]-6-fluoro-1 -[(1 R,2S)-2-fluorocyclopropyl]-l,4-dihydro-8-methoxy-4oxoquinoline-3-carboxylic acid, or a salt or a hydrate thereof;
7-[7-amino-7-methyl-5-azaspiro[2.4]heptane-5-yl]-l-[(lR,2S)-2-fluorocyclopropyl]-8-methyl-l,4-dihydro-4-oxoquinoline-3-carboxylic acid, or a salt or a hydrate thereof;
7-[7-amino-7-methyl-5-azaspiro[2.4]heptane-5-yl]-l-[(lR,2S)-2-fluorocyclopropyl]-8-methoxy-l,4-dihydro-4-oxoquinoline-3-carboxylic acid, or a salt or a hydrate thereof; 7-[7-amino-7-methyl-5-azaspiro[2.4]heptane-5-yl]-6-fluoro-l-[(lR,2S)-2-
fluorocyclopropyl]-l,4-dihydro-8-methyl-4-oxoquinoline-3-carboxylic acid, or a salt or
a hydrate thereof;
7-[7-amino-7-methyl-5-azaspiro[2.4]heptane-5-yl]-6-fluoro-l-[(lR,2S)-2-fluorocyclopropyl]-l,4-dihydro-8-methoxy-4oxoquinoline-3-carboxylic acid, or a salt or a hydrate thereof;
7-[8-amino-8-methyl-6-azaspiro[3.4]octane-5-yl]-6-fluoro-l-[(lR,2S)-2-fluorocyclopropyl]-l,4-dihydro-8-methyl-4-oxoquinoline-3-carboxylic acid, or a salt or a hydrate thereof; and
7-[8-amino-8-methyl-6-azaspiro[3.4]octane-5-yl]-6-fluoro-l[(lR,2S)-2-fluorocyclopropyl]-l,4-dihydro-8-methoxy-4oxoquinoline-3-carboxylic acid, or a salt or a hydrate thereof.
17. The compound, or a salt or a hydrate thereof as claimed in claim 16, wherein, in the compound of formula (I), absolute configuration at position 3 where amino group has substituted on the pyrroridine ring is (3R).
18. The compound, or a salt or a hydrate thereof as claimed in claim 16, wherein, in the compound of formula (I), absolute configuration at position 3 where amino group has substituted on the pyrroridine ring is (3S).

19. A compound as claimed in claim 1 selected from
7-[(7S)-7-amino-7-methyl-5-azaspiro[2.4]heptane-5-yl]-l-[(lR,2S)-2-fluorocyclopropyl]-
8-methyl-l,4-dihydro~4-oxoquinoline-3-carboxylic acid, or a salt or a hydrate thereof;
7-[(7S)-7-amino-7-methyl-5-azaspiro[2.4]heptane-5-y 1 ]-6-fl uoro-1 -[(1 R,2S)-2-fluorocyclopropyl]-8-methyl-l,4-dihydro-4-oxoquinoline-3-carboxylic acid, or a salt or a hydrate thereof;
7-[(7S)-7-amino-7-methyl-5-azaspiro[2.4]heptane-5-yl]-6-fluoro-l-[(lR,2S)-2-fluorocyclopropyl]-8-methoxy-l,4-dihydro-4-oxoquinoline-3-carboxylic acid, or a salt or a hydrate thereof;
7-[(7S)-7-amino-7-methyl-5-azaspiro[2.4]heptane-5-yl]-6-fluoro-l-[(lR,2S)-2-fluorocyclopropyl]-8-methoxy-l,4-dihydro-4-oxoquinoline-3-carboxylic acid, or a salt or a hydrate thereof.
20. The compound as claimed in claim 1 wherein it is 7-[(7S)-7-amino-7-methyl-5-
azaspiro [2.4 ]heptane-5-yl] -6-fluoro-1 -[(1 R,2 S)-2-fluorocyclopropyl] -8-methyl-1,4-
dihydro-4-oxoquinoline-3-carboxylic acid, or a salt or a hydrate thereof.
21. The compound as claimed in claim 1 wherein it is 7-[(7S)-7-amino-7-methyl-5-
azaspiro[2.4]heptane-5-yl]-6-fluoro-l-[(lR,2S)-2-fluorocyclopropyl]-8-methoxy-l,4-
dihydro-4-oxoquinoline-3-carboxylic acid, or a salt or a hydrate thereof.
22. The compound as claimed in claims 1 as and when used in the preparation of an antibacterial agent or a therapeutic agent.